rs148135241

chr1-216200074-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):c.3364T>G(p.Ser1122Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,840 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1122S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.99

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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 88) in uniprot entity USH2A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010767311).
• BP6: Variant 1-216200074-A-C is Benign according to our data. Variant chr1-216200074-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 48500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216200074-A-C is described in Lovd as [Benign]. Variant chr1-216200074-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00195 (297/152182) while in subpopulation EAS AF= 0.0489 (252/5158). AF 95% confidence interval is 0.0439. There are 8 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.3364T>G	p.Ser1122Ala	missense_variant	17/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+4149A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.3364T>G	p.Ser1122Ala	missense_variant	17/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.3364T>G	p.Ser1122Ala	missense_variant	17/21	1
USH2A-AS1	ENST00000420867.1	n.363-3956A>C		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.3364T>G	p.Ser1122Ala	missense_variant	17/73

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152064 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00446 AC: 1118 AN: 250806 Hom.: 29 AF XY: 0.00407 AC XY: 552 AN XY: 135554

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.0562

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00137 AC: 2002 AN: 1461658 Hom.: 39 Cov.: 31 AF XY: 0.00132 AC XY: 961 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.0403

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152182 Hom.: 8 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74410

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0489

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00226 Hom.: 14

Bravo AF: 0.00256

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00446 AC: 541

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2013	Ser1122Ala in Exon 17 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 6.0% (24/394) of Asian chromosomes from the 1000 Genomes Project (dbSNP rs148135241). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Usher syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 14, 2022

- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	0.061
Eigen_PC	Benign	-0.0094
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.055	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.43
MVP		0.89
MPC		0.030
ClinPred		0.053	T
GERP RS		2.2
Varity_R		0.085
gMVP		0.40

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: rs148135241; hg19: chr1-216373416; COSMIC: COSV56377413; COSMIC: COSV56377413;