17-74922980-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_173477.5(USH1G):c.94G>A(p.Gly32Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,407,906 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G32G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000055 ( 1 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.90

Publications

0 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 links:

OTOP2 (HGNC:19657): (otopetrin 2) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

OTOP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000554 (78/1407906) while in subpopulation SAS AF = 0.000948 (76/80176). AF 95% confidence interval is 0.000776. There are 1 homozygotes in GnomAdExome4. There are 59 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 1 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 link	c.-163G>A		5_prime_UTR_variant	Exon 1 of 3		NP_001269418.1	Q495M9B4DL95
USH1G	XM_011524296.2 link	c.-550G>A		upstream_gene_variant			XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH1G	ENST00000614341.5 link	c.94G>A	p.Gly32Ser	missense_variant	Exon 1 of 3	1	NM_173477.5	ENSP00000480279.1	Q495M9
OTOP2	ENST00000580223.2 link	c.-285C>T		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000463837.2	A0A6E1ZAN8
USH1G	ENST00000579243.1 link	n.94G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000132

AC:

AN:

174768

AF XY:

0.000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1407906

Hom.:

Cov.:

AF XY:

0.0000849

AC XY:

AN XY:

694822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32182

American (AMR)

AF:

0.00

AC:

AN:

37462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25226

East Asian (EAS)

AF:

0.00

AC:

AN:

36710

South Asian (SAS)

AF:

0.000948

AC:

AN:

80176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1082648

Other (OTH)

AF:

0.00

AC:

AN:

58268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000122

Hom.:

ExAC

AF:

0.000127

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.94G>A (p.G32S) alteration is located in exon 1 (coding exon 1) of the USH1G gene. This alteration results from a G to A substitution at nucleotide position 94, causing the glycine (G) at amino acid position 32 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine with serine at codon 32 of the USH1G protein (p.Gly32Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs752872097, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with USH1G-related conditions. ClinVar contains an entry for this variant (Variation ID: 1488686). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH1G protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.84

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.75

Gain of glycosylation at G32 (P = 0.0436);

MVP

0.52

ClinPred

0.40

GERP RS

4.1

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.89

gMVP

0.82

Mutation Taster

=49/51

disease causing

(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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17-74922980-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over