rs752996514

Positions:

• chr1-215817002-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_206933.4(USH2A):​c.9565G>T​(p.Ala3189Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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:2
• Conservation: PhyloP100: -0.420

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Fibronectin type-III 18 (size 96) in uniprot entity USH2A_HUMAN there are 24 pathogenic changes around while only 7 benign (77%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39990354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.9565G>T	p.Ala3189Ser	missense_variant	48/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.9565G>T	p.Ala3189Ser	missense_variant	48/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.9565G>T	p.Ala3189Ser	missense_variant	48/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250430 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

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: 0.00000137 AC: 2 AN: 1460212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2024

Variant summary: USH2A c.9565G>T (p.Ala3189Ser) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9565G>T has been reported in the literature in the compound heterozygous state in at least one individual affected with retinitis pigmentosa (e.g. Xu_2014). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 24938718). ClinVar contains an entry for this variant (Variation ID: 552654). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.8
DANN	Benign	0.92
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.28
Sift	Benign	0.48	T
Sift4G	Benign	0.82	T
Polyphen		0.016	B
Vest4		0.66
MutPred		0.44		Gain of disorder (P = 0.0224);
MVP		0.60
MPC		0.029
ClinPred		0.011	T
GERP RS		-2.0
Varity_R		0.041
gMVP		0.14

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: rs752996514; hg19: chr1-215990344; COSMIC: COSV105133971;