11-17509737-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_153676.4(USH1C):​c.1632C>A​(p.Asp544Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,601,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.194
• Publications: 3 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29712233).

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>A	p.Asp544Glu	missense	Exon 18 of 27	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1284+7664C>A		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1470+2165C>A		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>A	p.Asp544Glu	missense	Exon 18 of 27	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+7664C>A		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1227+7664C>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151598 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 4 AN: 240246 AF XY: 0.0000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1450210 Hom.: 0 Cov.: 40 AF XY: 0.0000249 AC XY: 18 AN XY: 721674

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

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

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 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: 0.00 AC: 0 AN: 1111848

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

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151598 Hom.: 0 Cov.: 29 AF XY: 0.0000270 AC XY: 2 AN XY: 73998

African (AFR) AF: 0.00 AC: 0 AN: 41216

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.29	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	0.70	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.19
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.14
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		0.92	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;