rs774005703

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153676.4(USH1C):​c.238C>T​(p.Arg80Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

3
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 5.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21843714).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH1CNM_153676.4 linkuse as main transcriptc.238C>T p.Arg80Trp missense_variant 3/27 ENST00000005226.12
USH1CNM_005709.4 linkuse as main transcriptc.238C>T p.Arg80Trp missense_variant 3/21 ENST00000318024.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH1CENST00000005226.12 linkuse as main transcriptc.238C>T p.Arg80Trp missense_variant 3/275 NM_153676.4 Q9Y6N9-5
USH1CENST00000318024.9 linkuse as main transcriptc.238C>T p.Arg80Trp missense_variant 3/211 NM_005709.4 P1Q9Y6N9-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152076
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.0000361
AC:
9
AN:
249530
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
134920
show subpopulations
Gnomad AFR exome
AF:
0.000434
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461228
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726830
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152194
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.000144
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
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 10, 2022This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 80 of the USH1C protein (p.Arg80Trp). This variant is present in population databases (rs774005703, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1009505). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Usher syndrome type 1C Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 21, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.19
T;.;.;.;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.22
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;.;N;N;.
MutationTaster
Benign
0.89
D;D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.5
D;D;N;N;N
REVEL
Benign
0.25
Sift
Uncertain
0.016
D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;.
Polyphen
1.0
D;.;D;.;.
Vest4
0.57
MVP
0.44
MPC
0.36
ClinPred
0.30
T
GERP RS
3.6
Varity_R
0.28
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs774005703; hg19: chr11-17552956; API