rs45549044

chr1-215671031-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206933.4(USH2A):c.14074G>A(p.Gly4692Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,614,064 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (39 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.48

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01668179).
• BP6: Variant 1-215671031-C-T is Benign according to our data. Variant chr1-215671031-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 48427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215671031-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.14074G>A	p.Gly4692Arg	missense_variant	64/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14074G>A	p.Gly4692Arg	missense_variant	64/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14074G>A	p.Gly4692Arg	missense_variant	64/73

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 642 AN: 152086 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00471 AC: 1182 AN: 250890 Hom.: 6 AF XY: 0.00494 AC XY: 670 AN XY: 135636

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00789

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00672 AC: 9817 AN: 1461860 Hom.: 39 Cov.: 31 AF XY: 0.00664 AC XY: 4831 AN XY: 727234

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00797

Gnomad4 OTH exome AF: 0.00588

GnomAD4 genome AF: 0.00421 AC: 641 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74406

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00745

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00643 Hom.: 9

Bravo AF: 0.00404

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00478 AC: 580

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00785

EpiControl AF: 0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2018	This variant is associated with the following publications: (PMID: 22004887, 25333064, 25262649, 24944099, 26927203, 19129697, 30245029, 32707200) -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 25, 2011	Gly4692Ar in Exon 64 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (53/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; rs45549044). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 26, 2022	Variant summary: USH2A c.14074G>A (p.Gly4692Arg) results in a non-conservative amino acid change located in the Fibronectin Type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 250890 control chromosomes in the gnomAD database, including 6 homozygotes. Although reported in the literature, to our knowledge, no penetrant association of c.14074G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 19, 2017	- -

Usher syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.43
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.76		Loss of sheet (P = 0.0357);
MVP		0.87
MPC		0.23
ClinPred		0.019	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.65

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: rs45549044; hg19: chr1-215844373; COSMIC: COSV56323371;