rs146333270

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_153676.4(USH1C):c.1430G>A(p.Arg477Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,896 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.22

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40767193).

BP6

Variant 11-17510505-C-T is Benign according to our data. Variant chr11-17510505-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47979.

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.1430G>A	p.Arg477Gln	missense	Exon 17 of 27	NP_710142.1
USH1C	NM_005709.4	MANE Plus Clinical	c.1284+6896G>A		intron	N/A	NP_005700.2
USH1C	NM_001440679.1		c.1470+1397G>A		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.1430G>A	p.Arg477Gln	missense	Exon 17 of 27	ENSP00000005226.7
USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+6896G>A		intron	N/A	ENSP00000317018.4
USH1C	ENST00000527020.5	TSL:1	c.1227+6896G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000750

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000286

AC:

AN:

251326

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000543

AC:

793

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000503

AC XY:

366

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.000403

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000659

AC:

733

AN:

1111834

Other (OTH)

AF:

0.000530

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000401

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41552

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.000538

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg477Gln variant (rs146333270) has been reported as a â€˜probably neutral variantâ€™ in at least one individual with Usher syndrome; however, inheritance and specific clinical information were not reported (Le Quesne Stabej 2012). The p.Arg477Gln variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.028% (identified in 77 out of 277,120 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 47979). The arginine at codon 477 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the USH1C protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Arg477Gln variant cannot be determined with certainty.

not specified

Uncertain:1

Apr 24, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg477Gln variant in USH1C has been previously reported by our laboratory in the heterozygous state in two individuals with hearing loss, one of whom har bored two pathogenic variants in another gene. This variant has been identified in 77/277120 of the total chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org/; dbSNP rs146333270). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the p.Arg477Gln variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, the clini cal significance of the p.Arg477Gln variant is uncertain. ACMG/AMP Criteria appl ied: PM2_Supporting; PP3.

Hearing impairment

Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting, PP3_Supporting

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.063

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.63

PhyloP100

7.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.4

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Benign

0.086

Vest4

0.76

MVP

0.56

MPC

0.40

ClinPred

0.19

GERP RS

5.9

gMVP

0.27

Mutation Taster

=68/32

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over