rs111033479

chr1-216421859-C-T

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.478G>A(p.Gly160Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. G160D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.38

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007727295).
• BP6: Variant 1-216421859-C-T is Benign according to our data. Variant chr1-216421859-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48522.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr1-216421859-C-T is described in Lovd as [Benign]. Variant chr1-216421859-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.478G>A	p.Gly160Ser	missense_variant	2/72	ENST00000307340.8
USH2A	NM_007123.6	c.478G>A	p.Gly160Ser	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.478G>A	p.Gly160Ser	missense_variant	2/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.478G>A	p.Gly160Ser	missense_variant	2/21	1
USH2A	ENST00000674083.1	c.478G>A	p.Gly160Ser	missense_variant	2/73

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

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: 0.0000147

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000582 AC: 146 AN: 250864 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135572

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.000289

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: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000195 AC: 285 AN: 1461646 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 127 AN XY: 727116

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.000336

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: 0.00000360

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74446

Gnomad4 AFR AF: 0.00751

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.00275

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 22, 2016	p.Gly160Ser in exon 2 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (85/10406) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs111033479). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 2A Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

USH2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.27
Sift	Benign	0.16	T;T
Sift4G	Benign	0.091	T;T
Polyphen		1.0	D;P
Vest4		0.20
MVP		0.84
MPC		0.069
ClinPred		0.028	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.59

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: rs111033479; hg19: chr1-216595201; COSMIC: COSV99048440;