chr11-17533268-G-A

Position:

chr11-17533268-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_153676.4(USH1C):c.91C>T(p.Arg31*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

USH1C
NM_153676.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.17

Variant links:

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]

USH1C links:

USH1C (HGNC:):

USH1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-17533268-G-A is Pathogenic according to our data. Variant chr11-17533268-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17533268-G-A is described in Lovd as [Pathogenic]. Variant chr11-17533268-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.91C>T	p.Arg31*	stop_gained	2/27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 linkuse as main transcript	c.91C>T	p.Arg31*	stop_gained	2/21	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.91C>T	p.Arg31*	stop_gained	2/27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.91C>T	p.Arg31*	stop_gained	2/21	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251248

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:2

Pathogenic, flagged submission	clinical testing	Baylor Genetics	Sep 07, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 23, 2018	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Arg31*) in the USH1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH1C are known to be pathogenic (PMID: 10973247, 17407589, 20301442, 21203349). This variant is present in population databases (rs121908370, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 11139240, 27440999, 27957503). ClinVar contains an entry for this variant (Variation ID: 5146). For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 1C

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 25, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -

Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

Vest4

0.79

GERP RS

5.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over