rs78253373

chr1-215674148-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):c.13763C>A(p.Ser4588Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00179 in 1,614,078 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.80

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=0.008418292).
• BP6: Variant 1-215674148-G-T is Benign according to our data. Variant chr1-215674148-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 48423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215674148-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00889 (1354/152230) while in subpopulation AFR AF= 0.0307 (1273/41526). AF 95% confidence interval is 0.0293. There are 24 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.13763C>A	p.Ser4588Tyr	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.13763C>A	p.Ser4588Tyr	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.13763C>A	p.Ser4588Tyr	missense_variant	63/73

Frequencies

GnomAD3 genomes AF: 0.00885 AC: 1346 AN: 152112 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00245 AC: 615 AN: 251246 Hom.: 6 AF XY: 0.00177 AC XY: 240 AN XY: 135770

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00105 AC: 1541 AN: 1461848 Hom.: 18 Cov.: 30 AF XY: 0.000941 AC XY: 684 AN XY: 727228

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000293

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00889 AC: 1354 AN: 152230 Hom.: 24 Cov.: 32 AF XY: 0.00861 AC XY: 641 AN XY: 74442

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.0689 Hom.: 2355

Bravo AF: 0.0100

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00292 AC: 354

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2015	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	Jun 21, 2011	Ser4588Tyr in exon 63 of USH2A: This variant is predicted to be benign based on its high frequency in the general population (dbSNP rs78253373). -

not provided Benign:2

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	Jul 15, 2022	- -

Usher syndrome type 2A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Retinitis pigmentosa 39 Benign:1

Likely 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	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.94
MPC		0.24
ClinPred		0.037	T
GERP RS		5.0
Varity_R		0.68
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs78253373; hg19: chr1-215847490; COSMIC: COSV56358824;