Genetic Variant NM_153676.4:c.684C>A (chr11-17524526-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_153676.4(USH1C):c.684C>A(p.Ser228Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S228S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.785

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 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	NM_153676.4	MANE Select	c.684C>A	p.Ser228Arg	missense	Exon 9 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.684C>A	p.Ser228Arg	missense	Exon 9 of 21	NP_005700.2
USH1C	NM_001440679.1		c.717C>A	p.Ser239Arg	missense	Exon 9 of 22	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.684C>A	p.Ser228Arg	missense	Exon 9 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.684C>A	p.Ser228Arg	missense	Exon 9 of 21	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.684C>A	p.Ser228Arg	missense	Exon 9 of 20	ENSP00000436934.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408040

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695252

African (AFR)

AF:

0.00

AC:

AN:

31934

American (AMR)

AF:

0.00

AC:

AN:

37682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25324

East Asian (EAS)

AF:

0.00

AC:

AN:

36386

South Asian (SAS)

AF:

0.00

AC:

AN:

79874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083038

Other (OTH)

AF:

0.00

AC:

AN:

58312

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

0.99

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.1

PhyloP100

-0.79

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.40

Sift

Benign

0.046

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.57

Gain of MoRF binding (P = 0.03)

MVP

0.40

MPC

0.41

ClinPred

0.97

GERP RS

-4.4

Varity_R

0.54

gMVP

0.88

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over