rs76769358

chr11-17504709-A-G

Variant summary

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

The NM_153676.4(USH1C):c.2134-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,541,542 control chromosomes in the GnomAD database, including 2,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (233 hom., cov: 33)
  • Exomes 𝑓: 0.067 (2553 hom.)
• Consequence: USH1C NM_153676.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002548
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.638

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17504709-A-G is Benign according to our data. Variant chr11-17504709-A-G is described in ClinVar as [Benign]. Clinvar id is 47989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17504709-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.1285-2729T>C		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.2134-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2134-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.1285-2729T>C		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7454 AN: 150088 Hom.: 234 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.0634

GnomAD3 exomes AF: 0.133 AC: 13967 AN: 104990 Hom.: 368 AF XY: 0.141 AC XY: 7920 AN XY: 56336

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.0665 AC: 92585 AN: 1391358 Hom.: 2553 Cov.: 36 AF XY: 0.0671 AC XY: 46470 AN XY: 692852

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0423

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.000185

Gnomad4 SAS exome AF: 0.0567

Gnomad4 FIN exome AF: 0.0484

Gnomad4 NFE exome AF: 0.0722

Gnomad4 OTH exome AF: 0.0655

GnomAD4 genome AF: 0.0496 AC: 7451 AN: 150184 Hom.: 233 Cov.: 33 AF XY: 0.0482 AC XY: 3536 AN XY: 73338

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.0556

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0548

Gnomad4 FIN AF: 0.0430

Gnomad4 NFE AF: 0.0713

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0564 Hom.: 33

Bravo AF: 0.0473

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 26, 2012	2134-12T>C in intron 21 of USH1C: This variant is not expected to have clinical significance because it has been identified in 7.7% (524/7020) of European Ameri can chromosomes and 1.7% (62/3738) of African American chromosomes in a broad po pulation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS /; dbSNP rs76769358). -

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	-0.86
Cadd	Benign	0.74
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0
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: rs76769358; hg19: chr11-17526256; COSMIC: COSV50030144; COSMIC: COSV50030144;