rs756163056

Positions:

• chr1-215817154-C-G
• chr1-215817154-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_206933.4(USH2A):​c.9413G>C​(p.Gly3138Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,586 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3138D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.69

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215817154-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9413G>C	p.Gly3138Ala	missense_variant	48/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9413G>C	p.Gly3138Ala	missense_variant	48/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9413G>C	p.Gly3138Ala	missense_variant	48/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460586 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726610

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Moderate, PP3_Supporting -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2022

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 3138 of the USH2A protein (p.Gly3138Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 866347). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function. 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. -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 30, 2019

- -

Usher syndrome type 2A 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.062	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.64		Loss of ubiquitination at K3135 (P = 0.0724);
MVP		0.95
MPC		0.24
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.39
gMVP		0.81

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: rs756163056; hg19: chr1-215990496; COSMIC: COSV56438014;