11-17531247-G-A

Position:

• chr11-17531247-G-A

Variant summary

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

The NM_153676.4(USH1C):​c.294C>T​(p.Leu98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,614,118 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (128 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (100 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.33

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-17531247-G-A is Benign according to our data. Variant chr11-17531247-G-A is described in ClinVar as [Benign]. Clinvar id is 48012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17531247-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.294C>T	p.Leu98=	synonymous_variant	4/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.294C>T	p.Leu98=	synonymous_variant	4/21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.294C>T	p.Leu98=	synonymous_variant	4/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.294C>T	p.Leu98=	synonymous_variant	4/21	1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3188 AN: 152172 Hom.: 128 Cov.: 33

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00554 AC: 1390 AN: 251106 Hom.: 58 AF XY: 0.00414 AC XY: 562 AN XY: 135830

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00215 AC: 3138 AN: 1461828 Hom.: 100 Cov.: 31 AF XY: 0.00185 AC XY: 1346 AN XY: 727228

Gnomad4 AFR exome AF: 0.0760

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00488

GnomAD4 genome AF: 0.0210 AC: 3197 AN: 152290 Hom.: 128 Cov.: 33 AF XY: 0.0206 AC XY: 1534 AN XY: 74460

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.00607

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00648 Hom.: 17

Bravo AF: 0.0243

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 07, 2011	Leu98Leu in exon 4 of USH1C: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located near a s plice junction and has a frequency of 2.2% (151/6811) of chromosomes from a broa d population (dbSNP rs34055234). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	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 1C Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0090
DANN	Benign	0.85

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: rs34055234; hg19: chr11-17552794;