Variant 17-74922974-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173477.5(USH1G):c.100A>T(p.Thr34Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,403,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5 linkuse as main transcript	c.100A>T	p.Thr34Ser	missense_variant	1/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 linkuse as main transcript	c.-157A>T		5_prime_UTR_variant	1/3		NP_001269418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
USH1G	ENST00000614341.5 linkuse as main transcript	c.100A>T	p.Thr34Ser	missense_variant	1/3	1	NM_173477.5	ENSP00000480279	P1
OTOP2	ENST00000580223.2 linkuse as main transcript	c.-291T>A		5_prime_UTR_variant	1/5	1		ENSP00000463837
USH1G	ENST00000579243.1 linkuse as main transcript	c.100A>T	p.Thr34Ser	missense_variant, NMD_transcript_variant	1/3	2		ENSP00000462568

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000591

AC:

AN:

169160

Hom.:

AF XY:

0.00

AC XY:

AN XY:

90068

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000805

Gnomad SAS 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:

0.00000142

AC:

AN:

1403672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000550

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.100A>T (p.T34S) alteration is located in exon 1 (coding exon 1) of the USH1G gene. This alteration results from a A to T substitution at nucleotide position 100, causing the threonine (T) at amino acid position 34 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

Sift4G

Uncertain

0.024

Polyphen

0.49

Vest4

0.62

MutPred

0.79

Gain of disorder (P = 0.0794);

MVP

0.42

ClinPred

0.92

GERP RS

4.1

Varity_R

0.56

gMVP

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over