chr1-215728189-T-A

Position:

• chr1-215728189-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206933.4(USH2A):​c.11907A>T​(p.Pro3969Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00823 in 1,614,098 control chromosomes in the GnomAD database, including 725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (381 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (344 hom.)
• Consequence: USH2A NM_206933.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.118

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-215728189-T-A is Benign according to our data. Variant chr1-215728189-T-A is described in ClinVar as [Benign]. Clinvar id is 48384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215728189-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.118 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.11907A>T	p.Pro3969Pro	synonymous_variant	61/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.11907A>T	p.Pro3969Pro	synonymous_variant	61/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.11907A>T	p.Pro3969Pro	synonymous_variant	61/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6138 AN: 152098 Hom.: 382 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0118 AC: 2957 AN: 251304 Hom.: 168 AF XY: 0.00881 AC XY: 1196 AN XY: 135816

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00914

GnomAD4 exome AF: 0.00489 AC: 7151 AN: 1461882 Hom.: 344 Cov.: 33 AF XY: 0.00429 AC XY: 3120 AN XY: 727244

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000795

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0403 AC: 6141 AN: 152216 Hom.: 381 Cov.: 32 AF XY: 0.0382 AC XY: 2843 AN XY: 74426

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0148 Hom.: 37

Bravo AF: 0.0468

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2011	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. -

Usher syndrome type 2A Benign:2

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

Retinitis pigmentosa 39 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
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.7
DANN	Benign	0.63

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: rs61635304; hg19: chr1-215901531;