chr11-17509462-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153676.4(USH1C):c.1907G>T(p.Arg636Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,485,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R636C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.523

Publications

1 publications found

Variant links:

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

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15969852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.1907G>T	p.Arg636Leu	missense_variant	Exon 18 of 27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.1285-7482G>T		intron_variant	Intron 15 of 20	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.1907G>T	p.Arg636Leu	missense_variant	Exon 18 of 27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.1285-7482G>T		intron_variant	Intron 15 of 20	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.0000145

AC:

AN:

138270

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000163

AC:

AN:

1347420

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

668574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30146

American (AMR)

AF:

0.00

AC:

AN:

41030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21950

East Asian (EAS)

AF:

0.00

AC:

AN:

29684

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.0000193

AC:

AN:

1037288

Other (OTH)

AF:

0.0000190

AC:

AN:

52738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000145

AC:

AN:

138270

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

66520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37738

American (AMR)

AF:

0.00

AC:

AN:

13228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3324

East Asian (EAS)

AF:

0.00

AC:

AN:

4080

South Asian (SAS)

AF:

0.00

AC:

AN:

3918

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.0000308

AC:

AN:

64836

Other (OTH)

AF:

0.00

AC:

AN:

1948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported using an alternate transcript of the gene -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.64

M_CAP

Benign

0.035

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

PhyloP100

0.52

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Uncertain

0.0050

Sift4G

Benign

0.45

Vest4

0.38

MutPred

0.46

Loss of catalytic residue at R636 (P = 0.0395);

MVP

0.42

MPC

0.077

ClinPred

0.99

GERP RS

3.7

gMVP

0.26

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over