Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_173477.5(USH1G):c.501C>G(p.Arg167Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,610,074 control chromosomes in the GnomAD database, including 12 homozygotes. 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 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 11 hom. )

Consequence

USH1G
NM_173477.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.875

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 17-74920335-G-C is Benign according to our data. Variant chr17-74920335-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48132.

BP7

Synonymous conserved (PhyloP=0.875 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152372) while in subpopulation NFE AF = 0.0027 (184/68040). AF 95% confidence interval is 0.00238. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173477.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	NM_173477.5	MANE Select	c.501C>G	p.Arg167Arg	synonymous	Exon 2 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.192C>G	p.Arg64Arg	synonymous	Exon 2 of 3	NP_001269418.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USH1G	ENST00000614341.5	TSL:1 MANE Select	c.501C>G	p.Arg167Arg	synonymous	Exon 2 of 3	ENSP00000480279.1
USH1G	ENST00000579243.1	TSL:2	n.*100C>G		non_coding_transcript_exon	Exon 2 of 3	ENSP00000462568.1
USH1G	ENST00000579243.1	TSL:2	n.*100C>G		3_prime_UTR	Exon 2 of 3	ENSP00000462568.1

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00157

AC:

388

AN:

246718

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.000505

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00244

AC:

3559

AN:

1457702

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1760

AN XY:

725122

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33430

American (AMR)

AF:

0.000627

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00220

AC:

190

AN:

86168

European-Finnish (FIN)

AF:

0.00153

AC:

AN:

50446

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00278

AC:

3094

AN:

1111212

Other (OTH)

AF:

0.00235

AC:

142

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

270

540

809

1079

1349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00185

AC:

282

AN:

152372

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41586

American (AMR)

AF:

0.00104

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00339

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00270

AC:

184

AN:

68040

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00195

Hom.:

Bravo

AF:

0.00162

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Usher syndrome type 1G (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.1

(source)

DANN

Benign

0.81

PhyloP100

0.88

Mutation Taster

=100/0

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

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

rs141688757

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