rs145114473

Positions:

chr1-216323538-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_206933.4(USH2A):c.1486A>C(p.Thr496Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.0690

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 67 pathogenic changes around while only 10 benign (87%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060578376).

BP6

Variant 1-216323538-T-G is Benign according to our data. Variant chr1-216323538-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48447.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.1486A>C	p.Thr496Pro	missense_variant	8/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6 linkuse as main transcript	c.1486A>C	p.Thr496Pro	missense_variant	8/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.1486A>C	p.Thr496Pro	missense_variant	8/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1486A>C	p.Thr496Pro	missense_variant	8/21	1		ENSP00000355909		O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1486A>C	p.Thr496Pro	missense_variant	8/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250894

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.000957

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000138

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.000507

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000392

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2023	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2010

Thr496Pro in USH2A: This variant is not expected to have clinical significance b ecause the Thr496 residue is not conserved in mammals and is a proline in lizard . -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.63

CADD

Benign

9.4

DANN

Benign

0.92

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.061

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.033

Sift

Benign

0.14

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0020

B;B

Vest4

0.18

MVP

0.84

MPC

0.036

ClinPred

0.0090

GERP RS

0.36

Varity_R

0.30

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over