rs200085788

Positions:

• chr11-17509629-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153676.4(USH1C):​c.1740T>C​(p.Pro580=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,232,128 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 13)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.674

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-17509629-A-G is Benign according to our data. Variant chr11-17509629-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 47981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.674 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00106 (65/61216) while in subpopulation EAS AF= 0.0208 (55/2644). AF 95% confidence interval is 0.0164. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 13. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.1740T>C	p.Pro580=	synonymous_variant	18/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-7649T>C		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1740T>C	p.Pro580=	synonymous_variant	18/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.1285-7649T>C		intron_variant		1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 65 AN: 61188 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000238

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00238

GnomAD3 exomes AF: 0.000884 AC: 174 AN: 196868 Hom.: 2 AF XY: 0.000732 AC XY: 79 AN XY: 107990

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.0000743

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000629

GnomAD4 exome AF: 0.000449 AC: 526 AN: 1170912 Hom.: 4 Cov.: 40 AF XY: 0.000420 AC XY: 242 AN XY: 576850

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000323

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0222

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000426

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00106 AC: 65 AN: 61216 Hom.: 0 Cov.: 13 AF XY: 0.00107 AC XY: 31 AN XY: 28920

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.000238

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0208

Gnomad4 SAS AF: 0.00267

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00235

Alfa AF: 0.00229 Hom.: 0

Asia WGS AF: 0.00809 AC: 28 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	USH1C: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 30, 2017

p.Pro580Pro in exon 18 of USH1C: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 1.2% (164/13838) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs200085788). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.38

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: rs200085788; hg19: chr11-17531176;