rs17776775

Positions:

• chr11-17509599-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.1770C>T​(p.Ala590Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 1,600,338 control chromosomes in the GnomAD database, including 3,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (212 hom., cov: 26)
  • Exomes 𝑓: 0.057 (3530 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.752

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]

USH1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 11-17509599-G-A is Benign according to our data. Variant chr11-17509599-G-A is described in ClinVar as [Benign]. Clinvar id is 47982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17509599-G-A is described in Lovd as [Benign]. Variant chr11-17509599-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.752 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1770C>T	p.Ala590Ala	synonymous_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-7619C>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1770C>T	p.Ala590Ala	synonymous_variant	18/27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1285-7619C>T		intron_variant		1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 5954 AN: 150506 Hom.: 212 Cov.: 26

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0341

Gnomad EAS AF: 0.0347

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0610 AC: 13848 AN: 227166 Hom.: 814 AF XY: 0.0687 AC XY: 8475 AN XY: 123390

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0270

Gnomad ASJ exome AF: 0.0363

Gnomad EAS exome AF: 0.0268

Gnomad SAS exome AF: 0.196

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.0521

Gnomad OTH exome AF: 0.0569

GnomAD4 exome AF: 0.0566 AC: 82057 AN: 1449716 Hom.: 3530 Cov.: 40 AF XY: 0.0605 AC XY: 43540 AN XY: 719888

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.0278

Gnomad4 ASJ exome AF: 0.0349

Gnomad4 EAS exome AF: 0.0359

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.0344

Gnomad4 NFE exome AF: 0.0505

Gnomad4 OTH exome AF: 0.0583

GnomAD4 genome AF: 0.0395 AC: 5948 AN: 150622 Hom.: 212 Cov.: 26 AF XY: 0.0406 AC XY: 2981 AN XY: 73470

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.0341

Gnomad4 EAS AF: 0.0347

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.0356

Gnomad4 NFE AF: 0.0491

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0470 Hom.: 61

Bravo AF: 0.0369

Asia WGS AF: 0.0990 AC: 345 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2013	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	Eurofins Ntd Llc (ga)	May 25, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Usher syndrome type 1C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.4
DANN	Benign	0.41

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: rs17776775; hg19: chr11-17531146; COSMIC: COSV50016008; COSMIC: COSV50016008;