rs3767698

Variant names:

• chr1-216325569-A-C
• rs3767698
• NM_206933.4:c.879T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_206933.4(USH2A):​c.879T>G​(p.Leu293Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,342 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (107 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.892
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-216325569-A-C is Benign according to our data. Variant chr1-216325569-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48609.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.879T>G	p.Leu293Leu	synonymous_variant	Exon 6 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.879T>G	p.Leu293Leu	synonymous_variant	Exon 6 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.879T>G	p.Leu293Leu	synonymous_variant	Exon 6 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.879T>G	p.Leu293Leu	synonymous_variant	Exon 6 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.879T>G	p.Leu293Leu	synonymous_variant	Exon 6 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152040 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00555 AC: 1387 AN: 249974 AF XY: 0.00497

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00691

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.0582

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00233 AC: 3400 AN: 1461184 Hom.: 107 Cov.: 31 AF XY: 0.00231 AC XY: 1676 AN XY: 726912

African (AFR) AF: 0.000209 AC: 7 AN: 33452

American (AMR) AF: 0.00647 AC: 289 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26118

East Asian (EAS) AF: 0.0675 AC: 2672 AN: 39612

South Asian (SAS) AF: 0.00253 AC: 218 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111624

Other (OTH) AF: 0.00263 AC: 159 AN: 60350

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152158 Hom.: 14 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74372

African (AFR) AF: 0.000434 AC: 18 AN: 41518

American (AMR) AF: 0.00288 AC: 44 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.0647 AC: 333 AN: 5144

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000592 Hom.: 1

Bravo AF: 0.00340

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 2A Uncertain:1 Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Sep 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.50
PhyloP100		-0.89
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3767698; hg19: chr1-216498911;