11-17523544-A-T

Variant names:

• chr11-17523544-A-T
• rs4757539
• NM_153676.4:c.760-66T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153676.4(USH1C):​c.760-66T>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.902
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.760-66T>A		intron_variant	Intron 9 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.760-66T>A		intron_variant	Intron 9 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.760-66T>A		intron_variant	Intron 9 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.760-66T>A		intron_variant	Intron 9 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.23e-7 AC: 1 AN: 1383748 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 691228

African (AFR) AF: 0.00 AC: 0 AN: 32054

American (AMR) AF: 0.00 AC: 0 AN: 43292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 82814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044630

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.41
DANN	Benign	0.53
PhyloP100		-0.90

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

Other links and lift over

dbSNP: rs4757539; hg19: chr11-17545091;