11-17509737-G-C

Variant names:

• chr11-17509737-G-C
• rs142545736
• NM_153676.4:c.1632C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153676.4(USH1C):​c.1632C>G​(p.Asp544Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,210 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D544D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.1632C>G	p.Asp544Glu	missense	Exon 18 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1284+7664C>G		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1470+2165C>G		intron	N/A	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1632C>G	p.Asp544Glu	missense	Exon 18 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+7664C>G		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1227+7664C>G		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450210 Hom.: 0 Cov.: 40 AF XY: 0.00000139 AC XY: 1 AN XY: 721674

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 29

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.19
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.22	T
Vest4		0.59
MutPred		0.16		Loss of helix (P = 0.0444)
MVP		0.39
MPC		0.36
ClinPred		0.99	D
GERP RS		0.53
gMVP		0.38
Mutation Taster		=81/19	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: rs142545736; hg19: chr11-17531284;