rs201104489

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_153676.4(USH1C):c.1597G>A(p.Ala533Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,592,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.61

Publications

2 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 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P
Usher syndrome type 1
Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12764347).

BP6

Variant 11-17509772-C-T is Benign according to our data. Variant chr11-17509772-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166382.

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	UniProt
USH1C	NM_153676.4	MANE Select	c.1597G>A	p.Ala533Thr	missense	Exon 18 of 27	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4	MANE Plus Clinical	c.1284+7629G>A		intron	N/A	NP_005700.2	A0A0S2Z4U9
USH1C	NM_001440679.1		c.1470+2130G>A		intron	N/A	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1597G>A	p.Ala533Thr	missense	Exon 18 of 27	ENSP00000005226.7	Q9Y6N9-5
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+7629G>A		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
USH1C	ENST00000527020.5	TSL:1	c.1227+7629G>A		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes

AF:

0.0000625

AC:

AN:

143958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000421

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000226

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000668

AC:

AN:

239666

AF XY:

0.0000459

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000421

AC:

AN:

1448000

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

720612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.000269

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39598

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41880

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1110746

Other (OTH)

AF:

0.0000997

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.0000625

AC:

AN:

144050

Hom.:

Cov.:

AF XY:

0.0000573

AC XY:

AN XY:

69852

show subpopulations

African (AFR)

AF:

0.0000264

AC:

AN:

37942

American (AMR)

AF:

0.000420

AC:

AN:

14274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4836

South Asian (SAS)

AF:

0.000226

AC:

AN:

4420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66642

Other (OTH)

AF:

0.00

AC:

AN:

1932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000959

Hom.:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.90

PhyloP100

3.6

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.96

REVEL

Benign

0.069

Sift

Uncertain

0.0010

Sift4G

Benign

0.27

Vest4

0.30

MVP

0.65

MPC

0.28

ClinPred

0.79

GERP RS

4.7

gMVP

0.41

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over