rs35309576

chr1-215741484-T-Achr1-215741484-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_206933.4(USH2A):c.11602A>T(p.Met3868Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,670 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3868V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -2.26

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 -1 ACMG points.

• PM1: In a domain Fibronectin type-III 24 (size 97) in uniprot entity USH2A_HUMAN there are 25 pathogenic changes around while only 6 benign (81%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029243022).
• BP6: Variant 1-215741484-T-A is Benign according to our data. Variant chr1-215741484-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228203.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.11602A>T	p.Met3868Leu	missense_variant	60/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.11602A>T	p.Met3868Leu	missense_variant	60/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.11602A>T	p.Met3868Leu	missense_variant	60/73

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151882 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251298 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461788 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151882 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74182

Gnomad4 AFR AF: 0.00

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: 0.0000441

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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	Invitae	Feb 02, 2022	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3868 of the USH2A protein (p.Met3868Leu). This variant is present in population databases (rs35309576, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 228203). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 20, 2015

p.Met3868Leu in exon 60 of USH2A: This variant is not expected to have clinical significance because methionine (Met) at position 3868 is not conserved in mamma ls or evolutionarily distant species and 3 species (opossum, turkey, and chicken ) carry a leucine (Leu), and computational prediction tools do not predict an im pact to the protein. In addition, this variant have been been identified in 3/6 6718 European chromosomes and a variant at the same amino acid position (p.Met38 68Val) has been identified in 23% (15353/66718) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3530 9576) supporting tolerance of variation at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.0020
Dann	Benign	0.50
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.60	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.024
Sift	Benign	0.91	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.32		Gain of catalytic residue at M3868 (P = 0.0468);
MVP		0.29
MPC		0.029
ClinPred		0.017	T
GERP RS		-9.7
Varity_R		0.073
gMVP		0.24

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

Other links and lift over

dbSNP: rs35309576; hg19: chr1-215914826; COSMIC: COSV56351829;