11-17494365-CAGA-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_153676.4(USH1C):c.2664_2666del(p.Leu889del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000011 in 1,450,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: USH1C NM_153676.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.68

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_153676.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_005709.4	c.1655_1657del	p.Phe552del	inframe_deletion	21/21	ENST00000318024.9
USH1C	NM_153676.4	c.2664_2666del	p.Leu889del	inframe_deletion	27/27	ENST00000005226.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2664_2666del	p.Leu889del	inframe_deletion	27/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1655_1657del	p.Phe552del	inframe_deletion	21/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000434 AC: 1 AN: 230174 Hom.: 0 AF XY: 0.00000804 AC XY: 1 AN XY: 124400

Gnomad AFR exome AF: 0.00

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: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1450644 Hom.: 0 AF XY: 0.0000111 AC XY: 8 AN XY: 720446

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: 0.0000136

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 04, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 554232). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Phe552*) in the USH1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1 amino acid(s) of the USH1C protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1474458620; hg19: chr11-17515912;