rs41303255

Positions:

• chr1-216175293-T-A
• chr1-216175293-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The NM_206933.4(USH2A):​c.4586A>T​(p.Lys1529Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,738 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 0.00900

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain Laminin G-like 1 (size 192) in uniprot entity USH2A_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007950932).
• BP6: Variant 1-216175293-T-A is Benign according to our data. Variant chr1-216175293-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48520.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4586A>T	p.Lys1529Ile	missense_variant	21/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4586A>T	p.Lys1529Ile	missense_variant	21/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4586A>T	p.Lys1529Ile	missense_variant	21/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.4586A>T	p.Lys1529Ile	missense_variant	21/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.4586A>T	p.Lys1529Ile	missense_variant	21/73			ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

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: 0.00143

GnomAD3 exomes AF: 0.000455 AC: 114 AN: 250490 Hom.: 1 AF XY: 0.000355 AC XY: 48 AN XY: 135366

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.000174

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: 0.000198 AC: 289 AN: 1461456 Hom.: 2 Cov.: 31 AF XY: 0.000177 AC XY: 129 AN XY: 727024

Gnomad4 AFR exome AF: 0.00699

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74452

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.000981

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: 0.00142

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.00218

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	This variant is associated with the following publications: (PMID: 26969326) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 2A Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2014	Lys1529Ile in Exon 21A of USH2A: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (30/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41303255). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2022	Variant summary: USH2A c.4586A>T (p.Lys1529Ile) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250490 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00046 vs 0.011), allowing no conclusion about variant significance. c.4586A>T has been reported in the literature as a heterozygous genotype in at-least one individual affected with Usher Syndrome who was compound heterozygous for two different causal variants in the USH2A gene (example, Sloan-Heggen_2016). Additionally, it has been reported as a heterozygous genotype in an individual with early onset severe retinal dystrophy (EOSRD) and no evidence of hearing defect who harbored a homozygous nonsense variant in the TTLL5 gene supporting a possible alternate etiology of disease (example, Smirnov_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and a majority consensus as benign/likely benign (n=5), (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 28, 2018

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.24
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.66	P;P
Vest4		0.39
MVP		0.95
MPC		0.081
ClinPred		0.077	T
GERP RS		-0.63
Varity_R		0.16
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs41303255; hg19: chr1-216348635;