rs199537187

Variant names:

• chr11-17523445-C-A
• NM_153676.4:c.793G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17523445-C-A
• chr11-17523445-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_153676.4(USH1C):​c.793G>T​(p.Asp265Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.97

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.793G>T	p.Asp265Tyr	missense_variant	Exon 10 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.793G>T	p.Asp265Tyr	missense_variant	Exon 10 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.793G>T	p.Asp265Tyr	missense_variant	Exon 10 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.793G>T	p.Asp265Tyr	missense_variant	Exon 10 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	L;.;L;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.99
MutPred		0.69		Gain of phosphorylation at D265 (P = 0.0841);.;Gain of phosphorylation at D265 (P = 0.0841);Gain of phosphorylation at D265 (P = 0.0841);.;
MVP		0.82
MPC		0.42
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17544992; COSMIC: COSV50020184; COSMIC: COSV50020184;