chr11-17527112-A-C

Variant names:

• chr11-17527112-A-C
• rs28671305
• NM_153676.4:c.497-72T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153676.4(USH1C):​c.497-72T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.037 (156 hom., cov: 9)
  • Exomes 𝑓: 0.022 (374 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 2 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4	c.497-72T>G		intron_variant	Intron 5 of 26	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.497-72T>G		intron_variant	Intron 5 of 20	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.497-72T>G		intron_variant	Intron 5 of 26	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.497-72T>G		intron_variant	Intron 5 of 20	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 2461 AN: 66538 Hom.: 154 Cov.: 9

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.0221

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00735

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0433

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0217 AC: 17158 AN: 791816 Hom.: 374 Cov.: 25 AF XY: 0.0220 AC XY: 8648 AN XY: 392992

African (AFR) AF: 0.0930 AC: 1745 AN: 18758

American (AMR) AF: 0.0359 AC: 889 AN: 24788

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 149 AN: 17144

East Asian (EAS) AF: 0.0991 AC: 2798 AN: 28230

South Asian (SAS) AF: 0.0260 AC: 1306 AN: 50182

European-Finnish (FIN) AF: 0.00595 AC: 178 AN: 29904

Middle Eastern (MID) AF: 0.0216 AC: 58 AN: 2690

European-Non Finnish (NFE) AF: 0.0157 AC: 9170 AN: 585890

Other (OTH) AF: 0.0253 AC: 865 AN: 34230

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0371 AC: 2470 AN: 66584 Hom.: 156 Cov.: 9 AF XY: 0.0390 AC XY: 1199 AN XY: 30752

African (AFR) AF: 0.0656 AC: 1135 AN: 17312

American (AMR) AF: 0.0453 AC: 288 AN: 6352

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 36 AN: 2000

East Asian (EAS) AF: 0.0920 AC: 222 AN: 2414

South Asian (SAS) AF: 0.0436 AC: 67 AN: 1538

European-Finnish (FIN) AF: 0.0173 AC: 62 AN: 3580

Middle Eastern (MID) AF: 0.00820 AC: 1 AN: 122

European-Non Finnish (NFE) AF: 0.0191 AC: 613 AN: 32056

Other (OTH) AF: 0.0448 AC: 38 AN: 848

Alfa AF: 0.282 Hom.: 68

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.75
DANN	Benign	0.076
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism

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: rs28671305; hg19: chr11-17548659; COSMIC: COSV50024155;