rs727504790

Positions:

• chr11-17509795-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153676.4(USH1C):​c.1574T>C​(p.Leu525Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000793 in 1,260,288 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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13692522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.1574T>C	p.Leu525Pro	missense_variant	18/27	ENST00000005226.12
USH1C	NM_005709.4	c.1284+7606T>C		intron_variant		ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.1574T>C	p.Leu525Pro	missense_variant	18/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1284+7606T>C		intron_variant		1	NM_005709.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.93e-7 AC: 1 AN: 1260288 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 625938

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: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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 05, 2013

Variant classified as Uncertain Significance - Favor Benign. The Leu525Pro varia nt in USH1C has not been previously reported in individuals with hearing loss. S equencing data from large population studies is insufficient to assess variant f requency. Computational analyses (biochemical amino acid properties, conservati on, AlignGVGD, PolyPhen2, and SIFT) suggest that the Leu525Pro variant may not i mpact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be d etermined with certainty; however based upon the computational assessments, we w ould lean towards a more likely benign role. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.027
Sift	Benign	0.16	T
Sift4G	Benign	0.30	T
Vest4		0.32
MutPred		0.19		Gain of relative solvent accessibility (P = 0.005);
MVP		0.39
MPC		0.098
ClinPred		0.91	D
GERP RS		3.0
gMVP		0.32

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: rs727504790; hg19: chr11-17531342;