rs11024318

Positions:

• chr11-17521006-C-T

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.1086-12G>A 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 0.0502 in 1,613,244 control chromosomes in the GnomAD database, including 3,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (909 hom., cov: 31)
  • Exomes 𝑓: 0.046 (2180 hom.)
• Consequence: USH1C NM_153676.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004067
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.118

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=-0.59).
• BP6: Variant 11-17521006-C-T is Benign according to our data. Variant chr11-17521006-C-T is described in ClinVar as [Benign]. Clinvar id is 47974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17521006-C-T is described in Lovd as [Benign]. Variant chr11-17521006-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_005709.4	c.1086-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4	c.1086-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000005226.12	NP_710142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1086-12G>A		splice_polypyrimidine_tract_variant, intron_variant		5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.1086-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.0861 AC: 13084 AN: 152014 Hom.: 897 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0208

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0852

GnomAD3 exomes AF: 0.0603 AC: 15159 AN: 251444 Hom.: 722 AF XY: 0.0550 AC XY: 7469 AN XY: 135904

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0313

Gnomad SAS exome AF: 0.0280

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0634

GnomAD4 exome AF: 0.0465 AC: 67897 AN: 1461112 Hom.: 2180 Cov.: 47 AF XY: 0.0454 AC XY: 33004 AN XY: 726884

Gnomad4 AFR exome AF: 0.196

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0869

Gnomad4 EAS exome AF: 0.0364

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0402

Gnomad4 OTH exome AF: 0.0567

GnomAD4 genome AF: 0.0864 AC: 13138 AN: 152132 Hom.: 909 Cov.: 31 AF XY: 0.0843 AC XY: 6271 AN XY: 74392

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0881

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.0206

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0402

Gnomad4 OTH AF: 0.0844

Alfa AF: 0.0617 Hom.: 167

Bravo AF: 0.0964

Asia WGS AF: 0.0420 AC: 144 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	PreventionGenetics, part of Exact Sciences	-	- -
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	Apr 30, 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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Autosomal recessive nonsyndromic hearing loss 18A 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	-0.59
CADD	Benign	11
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.020		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: rs11024318; hg19: chr11-17542553;