rs144467375

Positions:

• chr1-215630211-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_206933.4(USH2A):​c.15298-1176A>G variant causes a intron change. The variant allele was found at a frequency of 0.00062 in 468,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.15

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.15298-1176A>G		intron_variant		ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.15298-1176A>G		intron_variant		1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.15347A>G	p.Lys5116Arg	missense_variant	71/73

Frequencies

GnomAD3 genomes AF: 0.000593 AC: 90 AN: 151834 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000675 AC: 104 AN: 154148 Hom.: 1 AF XY: 0.000738 AC XY: 62 AN XY: 83992

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000427

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000574

Gnomad FIN exome AF: 0.000744

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000859

GnomAD4 exome AF: 0.000634 AC: 201 AN: 317026 Hom.: 0 Cov.: 0 AF XY: 0.000546 AC XY: 99 AN XY: 181168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000417

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000436

Gnomad4 FIN exome AF: 0.000215

Gnomad4 NFE exome AF: 0.000923

Gnomad4 OTH exome AF: 0.000471

GnomAD4 genome AF: 0.000592 AC: 90 AN: 151952 Hom.: 0 Cov.: 28 AF XY: 0.000552 AC XY: 41 AN XY: 74258

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000521

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jun 23, 2021

- -

Usher syndrome Benign:1

Likely benign, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144467375; hg19: chr1-215803553;