rs2041027

Positions:

• chr11-17531558-G-A
• chr11-17531558-G-C

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.105-16C>T 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 0.414 in 1,611,078 control chromosomes in the GnomAD database, including 138,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13292 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125698 hom.)
• Consequence: USH1C NM_153676.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.379

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=-0.82).
• BP6: Variant 11-17531558-G-A is Benign according to our data. Variant chr11-17531558-G-A is described in ClinVar as [Benign]. Clinvar id is 47972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17531558-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.105-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.105-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.105-16C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.105-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63368 AN: 151836 Hom.: 13285 Cov.: 32

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.424

GnomAD3 exomes AF: 0.420 AC: 104268 AN: 248282 Hom.: 22070 AF XY: 0.416 AC XY: 55952 AN XY: 134356

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.512

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.420

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.413 AC: 602910 AN: 1459122 Hom.: 125698 Cov.: 56 AF XY: 0.411 AC XY: 298527 AN XY: 725838

Gnomad4 AFR exome AF: 0.396

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.487

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.417 AC: 63392 AN: 151956 Hom.: 13292 Cov.: 32 AF XY: 0.417 AC XY: 30965 AN XY: 74268

Gnomad4 AFR AF: 0.394

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.511

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.498

Gnomad4 NFE AF: 0.414

Gnomad4 OTH AF: 0.422

Alfa AF: 0.419 Hom.: 18147

Bravo AF: 0.416

Asia WGS AF: 0.403 AC: 1402 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Usher syndrome type 1C Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.57

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: rs2041027; hg19: chr11-17553105; COSMIC: COSV50038647;