chr1-216321926-T-C

Position:

chr1-216321926-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_206933.4(USH2A):c.1601A>G(p.Tyr534Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Y534Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.88

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a disulfide_bond (size 16) in uniprot entity USH2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.1601A>G	p.Tyr534Cys	missense_variant	9/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 linkuse as main transcript	c.1601A>G	p.Tyr534Cys	missense_variant	9/21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.1601A>G	p.Tyr534Cys	missense_variant	9/72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1601A>G	p.Tyr534Cys	missense_variant	9/21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1601A>G	p.Tyr534Cys	missense_variant	9/73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251020

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000205

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000642

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 03, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 28, 2014

The p.Tyr534Cys variant in USH2A has not been previously reported in individuals with hearing loss but was reported in 1/11540 Latino chromosomes by the Exome A ggregation Consortium (http://exac.broadinstitute.org). Although this variant ha s been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the p.Tyr534Cys variant may impact the protein, though this informa tion is not predictive enough to determine pathogenicity. In summary, the clinic al significance of the p.Tyr534Cys variant is uncertain. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 15, 2017

- -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;P

Vest4

0.85

MutPred

0.54

Gain of catalytic residue at P533 (P = 0.0074);Gain of catalytic residue at P533 (P = 0.0074);

MVP

0.96

MPC

0.25

ClinPred

0.99

GERP RS

4.4

Varity_R

0.66

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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