NM_206933.4:c.12145G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_206933.4(USH2A):c.12145G>A(p.Ala4049Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4049S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:5

Conservation

PhyloP100: 6.58

Publications

3 publications found

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1766231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12145G>A	p.Ala4049Thr	missense_variant	Exon 62 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.12145G>A	p.Ala4049Thr	missense_variant	Exon 62 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.12145G>A	p.Ala4049Thr	missense_variant	Exon 62 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251032

AF XY:

0.0000885

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111986

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000571

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41560

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000616

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4049 of the USH2A protein (p.Ala4049Thr). This variant is present in population databases (rs143696882, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 28041643; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 229616). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic. -

Mar 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32581362, 28041643, 39858579, 32037395) -

Usher syndrome type 2A

Uncertain:2

Nov 01, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_206933.2(USH2A):c.12145G>A(A4049T) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. A4049T has been observed in cases with relevant disease (PMID: 28041643). Functional assessments of this variant are not available in the literature. A4049T has been observed in population frequency databases (gnomAD: AFR 0.17%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.12145G>A(A4049T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Mar 12, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_206933.2:c.12145G>A variant in the USH2A gene is a missense variant predicted to cause substitution of alanine by threonine at amino acid 4049 (p.Ala4049Thr). The filtering allele frequency (the lower threshold of the 95% CI of 169/75038) of the c.12145G>A variant in USH2A is 0.001974 for African/African American chromosomes by gnomAD v4.1.0, which is higher than the ClinGen Hearing Loss VCEP threshold ([>0.0007]) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). There is one homozygous observation in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.31, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. The variant has been reported in one proband with retinitis pigmentosa and a second variant, phase unknown (c.9785G>T, p.Gly3262Val) (PMID: 28041643; PMID: 32581362; PMID: 38219857). The variant was also found to co-occur, phase unknown, with c.2299del, p.Glu767SerfsTer21 in an individual from a cohort of inherited retinal degeneration patients, however case-level phenotypic details were not provided (PMID: 32037395). The variant was observed to co-occur, phase unknown, with c.12979del (p.Ser4327Profs*46) in a female (age 60’s) with peripheral field loss, bone spicules, optic nerve atrophy, abnormal fundus appearance (0.5 PM3 points); with c.3166C>T(p.Gln1056*), phase unknown, in a female (age 70s) with a clinical diagnosis of retinitis pigmentosa, night blindness, peripheral vision loss, central vision loss or uncorrectable visual acuity, attenuated vessels, optic disc pallor, and appearance of bone spicules (0.5 PM3 points); with c.4823A>G (p.His1608Arg), phase unknown, in a female (age 30’s) with clinical diagnosis of retinitis pigmentosa (0.5 PM3 points); and with c.10073G>A (p.Cys3358Tyr), phase unknown, in a male (60’s) with nyctalopia, peripheral field loss, central vision loss, deterioration of color vision, and sensorineural hearing loss (0.5 PM3 points) (Labcorp Genetics (formerly Invitae) internal data, SCV001414478.6). The variant has also been reported in the homozygous state in four cases: one female (age 50s) with adult-onset retinitis pigmentosa including nyctalopia, peripheral field loss, bone spicules/pigment clumping, optic nerve atrophy/optic disc pallor, and abnormal fundus appearance (0.5 PM3 points), one female (age 60s) with nyctalopia, photophobia, bone spicules, optic nerve atrophy, abnormal fundus appearance, attenuated vessels, and no known extraocular features (0.5 PM3 points), and in two cases with clinical diagnoses of retinitis pigmentosa (Labcorp Genetics (formerly Invitae) internal data, SCV001414478.6). The variant has also been observed in combination with a variant of uncertain significance, phase unknown, in cases with features of retinitis pigmentosa (Labcorp Genetics (formerly Invitae) internal data, SCV001414478.6). The variant has also been observed in the heterozygous state and in combination with a second variant (phase unknown) among individuals undergoing multigene panel testing for inherited retinal disorders (PreventionGenetics internal data, SCV004112640.1).In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive isolated retinitis pigmentosa and for autosomal recessive Usher syndrome type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1_Supporting, PM3_Strong (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025) -

Usher syndrome

Pathogenic:1

Mar 17, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH2A c.12145G>A (p.Ala4049Thr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251032 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00013 vs 0.011), allowing no conclusion about variant significance. c.12145G>A has been reported in the literature in individuals affected with clinical features of Retinitis Pigmentosa (Carss_2017, Zampaglione_2020, internal_testing). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 32176120, 32037395, 38219857, 32581362). ClinVar contains an entry for this variant (Variation ID: 229616). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 39

Pathogenic:1

Mar 22, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

USH2A-related disorder

Pathogenic:1

Jul 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The USH2A c.12145G>A variant is predicted to result in the amino acid substitution p.Ala4049Thr. This variant has been reported along with a second USH2A variant in individuals with retinal disease (Table S2 in Carss et al. 2017. PubMed ID: 28041643; Table S2 in Zampaglione et al. 2020. PubMed ID: 32037395; Table S2 in Turro et al. 2020. PubMed ID: 32581362). Here, at PreventionGenetics, we have observed this variant along with a pathogenic USH2A variant in multiple individuals being tested for retinal dystrophies (internal data). This variant is reported in 0.17% of alleles in individuals of African descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215853640-C-T). This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Uncertain:1

Feb 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala4049Thr va riant in USH2A has not been previously reported in individuals with hearing loss , but has been identified in 0.2% (17/10368) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143696882 ). Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of this variant cannot be determined with certainty; however, the frequ ency data suggest that it is more likely to be benign. -

Retinal dystrophy

Uncertain:1

Jul 23, 2019

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.72

MetaRNN

Benign

0.18

MetaSVM

Uncertain

-0.12

MutationAssessor

Pathogenic

3.7

PhyloP100

6.6

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.019

Sift4G

Benign

0.067

Polyphen

0.99

Vest4

0.43

MVP

0.95

MPC

0.21

ClinPred

0.38

GERP RS

5.3

Varity_R

0.50

gMVP

0.67

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over