1-215741541-GAA-GA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_206933.4(USH2A):c.11549-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,117,120 control chromosomes in the GnomAD database, including 134 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 20 hom., cov: 32)

Exomes 𝑓: 0.017 ( 114 hom. )

Consequence

USH2A
NM_206933.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.396

Publications

4 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: Benign. The variant received -16 ACMG points.

BP6

Variant 1-215741541-GA-G is Benign according to our data. Variant chr1-215741541-GA-G is described in ClinVar as Benign. ClinVar VariationId is 177774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0102 (1414/138782) while in subpopulation AMR AF = 0.0416 (580/13952). AF 95% confidence interval is 0.0388. There are 20 homozygotes in GnomAd4. There are 737 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.11549-5delT		splice_region_variant, intron_variant	Intron 59 of 71	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11549-5delT		splice_region_variant, intron_variant	Intron 59 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.11549-5delT		splice_region_variant, intron_variant	Intron 59 of 72			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1405

AN:

138720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.000304

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.000775

Gnomad MID

AF:

0.0103

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0520

AC:

6144

AN:

118084

AF XY:

0.0486

show subpopulations

Gnomad AFR exome

AF:

0.0225

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.0415

Gnomad EAS exome

AF:

0.0674

Gnomad FIN exome

AF:

0.0213

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0613

GnomAD4 exome

AF:

0.0171

AC:

16767

AN:

978338

Hom.:

114

Cov.:

AF XY:

0.0176

AC XY:

8548

AN XY:

485518

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0254

AC:

551

AN:

21704

American (AMR)

AF:

0.120

AC:

3540

AN:

29458

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

273

AN:

15984

East Asian (EAS)

AF:

0.0388

AC:

1002

AN:

25812

South Asian (SAS)

AF:

0.0464

AC:

2553

AN:

55048

European-Finnish (FIN)

AF:

0.0172

AC:

588

AN:

34236

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

4262

European-Non Finnish (NFE)

AF:

0.00966

AC:

7267

AN:

752256

Other (OTH)

AF:

0.0229

AC:

906

AN:

39578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.359

Heterozygous variant carriers

1483

2966

4449

5932

7415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.0102

AC:

1414

AN:

138782

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

737

AN XY:

66892

show subpopulations

African (AFR)

AF:

0.0109

AC:

413

AN:

37900

American (AMR)

AF:

0.0416

AC:

580

AN:

13952

Ashkenazi Jewish (ASJ)

AF:

0.000304

AC:

AN:

3286

East Asian (EAS)

AF:

0.0236

AC:

113

AN:

4784

South Asian (SAS)

AF:

0.0284

AC:

126

AN:

4440

European-Finnish (FIN)

AF:

0.000775

AC:

AN:

7746

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00212

AC:

135

AN:

63664

Other (OTH)

AF:

0.0195

AC:

AN:

1900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

131

197

262

328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0247

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 01, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

11549-5delT in intron 59 of USH2A: This variant is not expected to have clinica l significance because it has been identified in 2.0% (166/8241) of European Am erican chromosomes by the NHLBI Exome Sequencing Project, it occurs within a pol y-T tract, and is not predicted to impact splicing (http://evs.gs.washington.edu /EVS/; dbSNP rs34565443).

Aug 29, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Aug 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31054281)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome type 2A

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa 39

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.40

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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