rs56165709

Positions:

• chr11-17495613-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153676.4(USH1C):​c.2611G>A​(p.Ala871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,614,210 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (21 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.161

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007481545).
• BP6: Variant 11-17495613-C-T is Benign according to our data. Variant chr11-17495613-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=3}. Variant chr11-17495613-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0055 (8038/1461872) while in subpopulation NFE AF= 0.00669 (7444/1112006). AF 95% confidence interval is 0.00657. There are 21 homozygotes in gnomad4_exome. There are 3892 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2611G>A	p.Ala871Thr	missense_variant	26/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1646+1145G>A		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2611G>A	p.Ala871Thr	missense_variant	26/27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1646+1145G>A		intron_variant		1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00313 AC: 788 AN: 251482 Hom.: 0 AF XY: 0.00308 AC XY: 419 AN XY: 135918

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00550 AC: 8038 AN: 1461872 Hom.: 21 Cov.: 31 AF XY: 0.00535 AC XY: 3892 AN XY: 727236

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00303 AC XY: 226 AN XY: 74502

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00531

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00490 Hom.: 3

Bravo AF: 0.00359

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00524 AC: 45

ExAC AF: 0.00292 AC: 355

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Ala871Thr in Exon 26 of USH1C: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (35/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs56165709). In addition, this variant has be en reported in one individual with Usher type 1 who carried two other truncating USH1C variants assumed to explain disease, one in cis with Ala871Thr (Zwaenepoe le 2001). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	USH1C: BP4, BS1 -

Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 18, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Usher syndrome type 1C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 01, 2021

NM_005709.3(USH1C):c.1646+1145G>A is an intronic variant classified as a variant of uncertain significance in the context of USH1C-related disorders. c.1646+1145G>A has been observed in cases with relevant disease (PMID: 24416283, 25333064). Functional assessments of this variant are not available in the literature. c.1646+1145G>A has been observed in population frequency databases (gnomAD: NFE 0.53%). In summary, there is insufficient evidence to classify NM_005709.3(USH1C):c.1646+1145G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

USH1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.010
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Vest4		0.29
MVP		0.20
MPC		0.061
ClinPred		0.0037	T
GERP RS		1.5
gMVP		0.51

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: rs56165709; hg19: chr11-17517160;