11-17494375-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153676.4(USH1C):c.2657A>G(p.Asp886Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 missense, splice_region
• Scores: Splicing: ADA: 0.02682
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39933497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.2657A>G	p.Asp886Gly	missense_variant, splice_region_variant	27/27	ENST00000005226.12
USH1C	NM_005709.4	c.1648A>G	p.Thr550Ala	missense_variant, splice_region_variant	21/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2657A>G	p.Asp886Gly	missense_variant, splice_region_variant	27/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1648A>G	p.Thr550Ala	missense_variant, splice_region_variant	21/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446374 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 717856

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2022

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 550 of the USH1C protein (p.Thr550Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	D;D;D;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.11
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.024	D
Vest4		0.45
MutPred		0.29		Loss of stability (P = 0.0465);
MVP		0.51
MPC		0.079
ClinPred		0.96	D
GERP RS		5.6
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.027
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.080		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: rs1055121763; hg19: chr11-17515922;