chr11-17517424-C-T

Position:

• chr11-17517424-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005709.4(USH1C):​c.1261G>A​(p.Gly421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,593,664 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (71 hom.)
• Consequence: USH1C NM_005709.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026290119).
• BP6: Variant 11-17517424-C-T is Benign according to our data. Variant chr11-17517424-C-T is described in ClinVar as [Benign]. Clinvar id is 45426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_005709.4	c.1261G>A	p.Gly421Ser	missense_variant	15/21	ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4	c.1211-1134G>A		intron_variant		ENST00000005226.12	NP_710142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000318024.9	c.1261G>A	p.Gly421Ser	missense_variant	15/21	1	NM_005709.4	ENSP00000317018.4
USH1C	ENST00000005226.12	c.1211-1134G>A		intron_variant		5	NM_153676.4	ENSP00000005226.7

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2225 AN: 152172 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00397 AC: 869 AN: 219106 Hom.: 28 AF XY: 0.00318 AC XY: 374 AN XY: 117712

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00287

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00184 AC: 2654 AN: 1441374 Hom.: 71 Cov.: 32 AF XY: 0.00165 AC XY: 1177 AN XY: 714746

Gnomad4 AFR exome AF: 0.0539

Gnomad4 AMR exome AF: 0.00374

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000310

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.0147 AC: 2232 AN: 152290 Hom.: 66 Cov.: 32 AF XY: 0.0147 AC XY: 1095 AN XY: 74466

Gnomad4 AFR AF: 0.0494

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00346 Hom.: 18

Bravo AF: 0.0168

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0423 AC: 186

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.00434 AC: 526

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	May 14, 2012	Gly421Ser in Exon 15B of USH1C: This variant is not expected to have clinical si gnificance because it has been identified in 4.3% (162/3734) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs115931035). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2016	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	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Usher syndrome type 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Benign	0.46
DEOGEN2	Benign	0.045	T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;.
PROVEAN	Benign	0.75	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.90	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0050	B;.;B
Vest4		0.14
MVP		0.18
ClinPred		0.0016	T
GERP RS		3.6
Varity_R		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs115931035; hg19: chr11-17538971;