rs139996942

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153676.4(USH1C):c.1859G>T(p.Arg620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 581,820 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R620C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 18 hom., cov: 0)

Exomes 𝑓: 0.0025 ( 25 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.34

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004986495).

BP6

Variant 11-17509510-C-A is Benign according to our data. Variant chr11-17509510-C-A is described in ClinVar as Benign. ClinVar VariationId is 166377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

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.1859G>T	p.Arg620Leu	missense	Exon 18 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7530G>T		intron	N/A	NP_005700.2
USH1C	NM_001440679.1		c.1470+2392G>T		intron	N/A	NP_001427608.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1859G>T	p.Arg620Leu	missense	Exon 18 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7530G>T		intron	N/A	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.1228-7530G>T		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

1366

AN:

35200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000969

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0529

GnomAD2 exomes

AF:

0.00276

AC:

631

AN:

228446

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.000553

GnomAD4 exome

AF:

0.00254

AC:

1388

AN:

546578

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

592

AN XY:

279170

show subpopulations

African (AFR)

AF:

0.0705

AC:

1172

AN:

16630

American (AMR)

AF:

0.00259

AC:

AN:

30084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10910

East Asian (EAS)

AF:

0.00

AC:

AN:

10764

South Asian (SAS)

AF:

0.000303

AC:

AN:

46198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25162

Middle Eastern (MID)

AF:

0.00134

AC:

AN:

2974

European-Non Finnish (NFE)

AF:

0.0000235

AC:

AN:

383108

Other (OTH)

AF:

0.00535

AC:

111

AN:

20748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

147

221

294

368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.0389

AC:

1370

AN:

35242

Hom.:

Cov.:

AF XY:

0.0382

AC XY:

642

AN XY:

16810

show subpopulations

African (AFR)

AF:

0.125

AC:

1306

AN:

10428

American (AMR)

AF:

0.0156

AC:

AN:

2504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

918

East Asian (EAS)

AF:

0.00

AC:

AN:

1586

South Asian (SAS)

AF:

0.000967

AC:

AN:

1034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

16978

Other (OTH)

AF:

0.0519

AC:

AN:

424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00177

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0316

AC:

139

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.99

REVEL

Benign

0.23

Sift

Uncertain

0.0030

Sift4G

Benign

0.13

Vest4

0.66

MVP

0.58

MPC

0.080

ClinPred

0.016

GERP RS

5.9

gMVP

0.27

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over