rs2355022

Positions:

• chr11-17533369-C-A

Variant summary

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

The ENST00000527720.5(USH1C):​c.-104G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,379,894 control chromosomes in the GnomAD database, including 12,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (982 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11686 hom.)
• Consequence: USH1C ENST00000527720.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.769

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=-0.89).
• BP6: Variant 11-17533369-C-A is Benign according to our data. Variant chr11-17533369-C-A is described in ClinVar as [Benign]. Clinvar id is 262735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17533369-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.37-47G>T		intron_variant		ENST00000318024.9
USH1C	NM_153676.4	c.37-47G>T		intron_variant		ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.37-47G>T		intron_variant		5	NM_153676.4
USH1C	ENST00000318024.9	c.37-47G>T		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15345 AN: 146812 Hom.: 980 Cov.: 31

Gnomad AFR AF: 0.0712

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0860

Gnomad ASJ AF: 0.0852

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.138

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0968

GnomAD3 exomes AF: 0.126 AC: 29540 AN: 233934 Hom.: 2703 AF XY: 0.134 AC XY: 17113 AN XY: 127420

Gnomad AFR exome AF: 0.0771

Gnomad AMR exome AF: 0.0743

Gnomad ASJ exome AF: 0.0942

Gnomad EAS exome AF: 0.0595

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.125 AC: 153849 AN: 1232970 Hom.: 11686 Cov.: 17 AF XY: 0.129 AC XY: 80407 AN XY: 625138

Gnomad4 AFR exome AF: 0.0625

Gnomad4 AMR exome AF: 0.0756

Gnomad4 ASJ exome AF: 0.0903

Gnomad4 EAS exome AF: 0.0580

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.104 AC: 15346 AN: 146924 Hom.: 982 Cov.: 31 AF XY: 0.108 AC XY: 7736 AN XY: 71818

Gnomad4 AFR AF: 0.0710

Gnomad4 AMR AF: 0.0859

Gnomad4 ASJ AF: 0.0852

Gnomad4 EAS AF: 0.0637

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0997

Alfa AF: 0.0104 Hom.: 10

Bravo AF: 0.111

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.89
CADD	Benign	1.7
DANN	Benign	0.45

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: rs2355022; hg19: chr11-17554916;