11-17501129-G-T

Position:

• chr11-17501129-G-T

Variant summary

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

The NM_153676.4(USH1C):​c.2302C>A​(p.Leu768Met) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632

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 (HGNC:):

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=0.3726222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2302C>A	p.Leu768Met	missense_variant	23/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1402C>A	p.Leu468Met	missense_variant	18/21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2302C>A	p.Leu768Met	missense_variant	23/27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1402C>A	p.Leu468Met	missense_variant	18/21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2015

The p.Leu768Met variant in USH1C has not been previously reported in individuals with hearing loss or Usher syndrome or in large population studies. Computation al prediction tools and conservation analyses suggest that the p.Leu768Met varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Leu768 Met variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.51	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.51	P;.;P;.
Vest4		0.43
MutPred		0.72		Gain of disorder (P = 0.1152);.;.;.;
MVP		0.27
MPC		0.32
ClinPred		0.83	D
GERP RS		-0.31
Varity_R		0.20
gMVP		0.60

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

Other links and lift over

dbSNP: rs876658110; hg19: chr11-17522676;