17-74919824-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173477.5(USH1G):c.1012G>A(p.Gly338Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000386 in 1,613,010 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.45

Publications

3 publications found

Variant links:

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USH1G Gene-Disease associations (from GenCC):

Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Usher syndrome type 1G
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

USH1G 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=0.004409492).

BP6

Variant 17-74919824-C-T is Benign according to our data. Variant chr17-74919824-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000663 (101/152342) while in subpopulation AMR AF = 0.00261 (40/15306). AF 95% confidence interval is 0.00197. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
USH1G	NM_173477.5 link	c.1012G>A	p.Gly338Arg	missense_variant	Exon 2 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 link	c.703G>A	p.Gly235Arg	missense_variant	Exon 2 of 3		NP_001269418.1
USH1G	XM_011524296.2 link	c.703G>A	p.Gly235Arg	missense_variant	Exon 2 of 3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
USH1G	ENST00000614341.5 link	c.1012G>A	p.Gly338Arg	missense_variant	Exon 2 of 3	1	NM_173477.5	ENSP00000480279.1
USH1G	ENST00000579243.1 link	n.*611G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2		ENSP00000462568.1
USH1G	ENST00000579243.1 link	n.*611G>A		3_prime_UTR_variant	Exon 2 of 3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000749

AC:

187

AN:

249690

AF XY:

0.000687

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00787

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.000357

AC:

521

AN:

1460668

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

258

AN XY:

726676

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00204

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00785

AC:

205

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000148

AC:

165

AN:

1111926

Other (OTH)

AF:

0.000961

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000663

AC:

101

AN:

152342

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41582

American (AMR)

AF:

0.00261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68032

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000854

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 13, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly338Arg variant in USH1G is not expected to have clinical significance b ecause it has been identified in 0.75% (76/10120) of Ashkenazi Jewish chromosome s including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs151242039). The glycine (Gly) at position 338 is not well conserved in mammals or evolutionary distant species, and at least 2 ma mmals (lesser Egyptian jerboa, elephant) carry an arginine (Arg), supporting tha t the change at this position is tolerated. -

Jan 06, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Dec 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17896313) -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

USH1G-related disorder

Benign:1

Dec 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.051

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.73

M_CAP

Benign

0.014

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

PhyloP100

4.5

PrimateAI

Uncertain

0.56

Sift4G

Uncertain

0.043

Polyphen

0.0

Vest4

0.31

MutPred

0.35

Gain of sheet (P = 0.0166);

MVP

0.28

ClinPred

0.021

GERP RS

3.3

Varity_R

0.11

gMVP

0.39

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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