rs397517880

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM5PP3BP4_StrongBP6BS1BS2

The NM_153676.4(USH1C):c.307C>T(p.Arg103Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00053 in 1,614,136 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 7 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.76

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17531233-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39427.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1, Likely_pathogenic=3}.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Dann, FATHMM_MKL, M_CAP, PrimateAI, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.022108346).

BP6

Variant 11-17531234-G-A is Benign according to our data. Variant chr11-17531234-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48013.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=2}. Variant chr11-17531234-G-A is described in Lovd as [Benign]. Variant chr11-17531234-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000564 (824/1461838) while in subpopulation SAS AF= 0.00785 (677/86258). AF 95% confidence interval is 0.00736. There are 7 homozygotes in gnomad4_exome. There are 547 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	4/27	ENST00000005226.12
USH1C	NM_005709.4 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	4/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	4/27	5	NM_153676.4		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	4/21	1	NM_005709.4	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00105

AC:

263

AN:

251126

Hom.:

AF XY:

0.00130

AC XY:

176

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00836

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000564

AC:

824

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

547

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00785

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000210

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	This variant is associated with the following publications: (PMID: 32467589, 30245029, 24498627) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2018	The USH1C c.307C>T; p.Arg103Cys variant (rs397517880) has been reported in the heterozygous state in a single individual diagnosed with Usher Syndrome type I (Besnard 2014). Another variant affecting this codon, Arg103His, has also been reported in two individuals with Usher Syndrome (Roux 2006, Saihan 2011). However, this variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.8% (identified on 261 out of 30,776 chromosomes, including 3 homozygotes) and is classified as a variant of uncertain significance in ClinVar (ID: 48013). The arginine at position 103 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg103Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg103Cys variant cannot be determined with certainty. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 04, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Arg103Cys v ariant in USH1C has been reported in one French individual with Usher syndrome t ype I (Besnard 2014) and has been identified in one Indian individual with senso rineural hearing loss by our laboratory (LMM unpublished data); however a second variant in USH1C was not detected in either individual. This variant is absent from large population studies. Another amino acid change at this position (Arg10 3His) has been identified in two individuals with Usher syndrome who were compou nd heterozygous with another pathogenic USH1C (Roux 2006, Saihan 2011), and the variant segregated with disease in an affected sibling of one of those individua ls (Saihain 2011). These data suggest that variants that alter the arginine resi due at position 103 may not be tolerated. Computational prediction tools and con servation analyses suggest that the Arg103Cys variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, while there is some suspicion for a pathogenic role, the clinical signifi cance of the Arg103Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;.;.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.022

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.2

L;.;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.4

D;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;D;.;.

Vest4

0.96

MutPred

0.78

Loss of methylation at R103 (P = 0.0217);.;Loss of methylation at R103 (P = 0.0217);Loss of methylation at R103 (P = 0.0217);.;

MVP

0.62

MPC

0.45

ClinPred

0.17

GERP RS

4.5

Varity_R

0.91

gMVP

0.77

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

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