chr1-216097127-G-A

Position:

chr1-216097127-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBP2

This summary comes from the ClinGen Evidence Repository: The p.Leu1572Phe variant in USH2A gene has a filtering allele frequency= 0.12% in Latino in gnomAD (54/35388 with 95% CI) which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1 supporting). It was reported in multiple publications as a polymorphism or as non-pathogenic based on detection among normal control chromosomes or other evidence (PMID:18273898, 19881469 and 17085681). Although the variant was reported in trans with c.2299delG in one patient diagnosed with Usher syndrome type II and in another with unclassified Usher syndrome (PMID:25097241 and 28944237), it was also identified in cis with c.2299delG; p.Glu767Serfs and in unknown configuration with c.2299delG and a stop codon (PMID:25472526), both in patients with Usher syndrome type II (BP2; PMID:20507924, 25097241, 17405132 and 26969326). Computational prediction using REVEL was 0.65 which did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive Usher syndrome, type 2A based on the HL EP-specified ACMG/AMP criteria applied (BS1, BP2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA143497/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:9O:1

Conservation

PhyloP100: 2.40

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 -2 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.4714C>T	p.Leu1572Phe	missense_variant	22/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.4714C>T	p.Leu1572Phe	missense_variant	22/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.4714C>T	p.Leu1572Phe	missense_variant	22/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000776

AC:

195

AN:

251270

Hom.:

AF XY:

0.000766

AC XY:

104

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00153

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:

0.00111

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00112

AC:

1643

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

788

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000591

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000971

Hom.:

Bravo

AF:

0.000771

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000782

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.000652

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	This variant is associated with the following publications: (PMID: 25472526, 25097241, 22025579, 26667666, 26969326, 28944237, 20145675, 22004887, 11311042, 17085681, 29953849, 30245029, 33576794) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	USH2A: BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 08, 2008	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2014

- -

Usher syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jul 28, 2019

The p.Leu1572Phe variant in USH2A gene has a filtering allele frequency= 0.12% in Latino in gnomAD (54/35388 with 95% CI) which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1 supporting). It was reported in multiple publications as a polymorphism or as non-pathogenic based on detection among normal control chromosomes or other evidence (PMID: 18273898, 19881469 and 17085681). Although the variant was reported in trans with c.2299delG in one patient diagnosed with Usher syndrome type II and in another with unclassified Usher syndrome (PMID: 25097241 and 28944237), it was also identified in cis with c.2299delG; p.Glu767Serfs and in unknown configuration with c.2299delG and a stop codon (PMID: 25472526), both in patients with Usher syndrome type II (BP2; PMID: 20507924, 25097241, 17405132 and 26969326). Computational prediction using REVEL was 0.65 which did not meet the Hearing Loss Expert Panel (HL EP) specified threshold of >0.7 for PP3. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive Usher syndrome, type 2A based on the HL EP-specified ACMG/AMP criteria applied (BS1, BP2). -

Retinitis pigmentosa

Benign:1

Likely benign, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.66

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0090

Polyphen

0.98

Vest4

0.55

MVP

0.89

MPC

0.23

ClinPred

0.074

GERP RS

4.0

Varity_R

0.38

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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