rs111033498

Positions:

• chr1-215640566-G-A
• chr1-215640566-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206933.4(USH2A):​c.14960C>T​(p.Ala4987Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,720 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4987A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0062 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (87 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026477277).
• BP6: Variant 1-215640566-G-A is Benign according to our data. Variant chr1-215640566-G-A is described in ClinVar as [Benign]. Clinvar id is 48451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215640566-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.14960C>T	p.Ala4987Val	missense_variant	68/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14960C>T	p.Ala4987Val	missense_variant	68/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14960C>T	p.Ala4987Val	missense_variant	68/73

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 933 AN: 151838 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00690 AC: 1723 AN: 249782 Hom.: 57 AF XY: 0.00523 AC XY: 706 AN XY: 135110

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.00177 AC: 2586 AN: 1461764 Hom.: 87 Cov.: 32 AF XY: 0.00149 AC XY: 1085 AN XY: 727192

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.0514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.00620 AC: 942 AN: 151956 Hom.: 29 Cov.: 31 AF XY: 0.00703 AC XY: 522 AN XY: 74256

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.0543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.000380 Hom.: 1

Bravo AF: 0.00866

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2011	Ala4987Val in exon 68 of USH2A: This variant is not expected to have clinical si gnificance because this residue is not highly conserved across species. Of note, chicken and frog have an aspartic acid at this position. In addition, the varia nt has been identified by our laboratory in 5/223 (2.3%) probands including 3/31 (9.7%) Hispanic probands. -

Retinitis pigmentosa 39 Benign:1

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

- -

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	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.76	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.43	T
Sift4G	Benign	0.28	T
Polyphen		0.0060	B
Vest4		0.14
MVP		0.73
MPC		0.030
ClinPred		0.0065	T
GERP RS		0.60
Varity_R		0.023
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111033498; hg19: chr1-215813908; COSMIC: COSV56353125;