rs115884084

Positions:

• chr1-215675466-A-G

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.12445T>C​(p.Trp4149Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,074 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (21 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.216

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 Benign. Variant got -18 ACMG points.

• PM1: In a domain Fibronectin type-III 26 (size 85) in uniprot entity USH2A_HUMAN there are 38 pathogenic changes around while only 10 benign (79%) in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058915615).
• BP6: Variant 1-215675466-A-G is Benign according to our data. Variant chr1-215675466-A-G is described in ClinVar as [Benign]. Clinvar id is 48399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215675466-A-G is described in Lovd as [Likely_benign]. Variant chr1-215675466-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0088 (1340/152274) while in subpopulation AFR AF= 0.0304 (1264/41548). AF 95% confidence interval is 0.029. There are 23 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.12445T>C	p.Trp4149Arg	missense_variant	63/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.12445T>C	p.Trp4149Arg	missense_variant	63/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.12445T>C	p.Trp4149Arg	missense_variant	63/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152156 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.000118

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00226 AC: 567 AN: 250364 Hom.: 7 AF XY: 0.00185 AC XY: 250 AN XY: 135316

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000969 AC: 1417 AN: 1461800 Hom.: 21 Cov.: 37 AF XY: 0.000854 AC XY: 621 AN XY: 727190

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00880 AC: 1340 AN: 152274 Hom.: 23 Cov.: 32 AF XY: 0.00866 AC XY: 645 AN XY: 74468

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00148 Hom.: 6

Bravo AF: 0.00971

ESP6500AA AF: 0.0263 AC: 116

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 18723146, 22139616, 25262649) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Trp4149Arg in Exon 63 of USH2A: This variant is not expected to have clinical si gnificance because it has been identified in 2.7% (100/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs115884084). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2022	Variant summary: USH2A c.12445T>C (p.Trp4149Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250364 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in USH2A causing Usher Syndrome phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature, to our knowledge, no penetrant association of c.12445T>C in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.34
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.069
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.34		Gain of disorder (P = 0.0052);
MVP		0.67
MPC		0.043
ClinPred		0.0043	T
GERP RS		-1.2
Varity_R		0.083
gMVP		0.62

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: rs115884084; hg19: chr1-215848808;