17-74923004-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_173477.5(USH1G):c.70G>A(p.Glu24Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,573,542 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

USH1G
NM_173477.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26241255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3 link	c.-187G>A		5_prime_UTR_variant	Exon 1 of 3		NP_001269418.1	Q495M9B4DL95
USH1G	XM_011524296.2 link	c.-574G>A		upstream_gene_variant			XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH1G	ENST00000614341.5 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	1	NM_173477.5	ENSP00000480279.1	Q495M9
OTOP2	ENST00000580223.2 link	c.-261C>T		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000463837.2	A0A6E1ZAN8
USH1G	ENST00000579243.1 link	n.70G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32668

American (AMR)

AF:

0.00

AC:

AN:

39450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25450

East Asian (EAS)

AF:

0.00

AC:

AN:

37680

South Asian (SAS)

AF:

0.00

AC:

AN:

81218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090294

Other (OTH)

AF:

0.00

AC:

AN:

58672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.70G>A (p.E24K) 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 70, causing the glutamic acid (E) at amino acid position 24 to be replaced by a lysine (K). 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

0.71

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.013

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

7.9

PrimateAI

Uncertain

0.77

Sift4G

Uncertain

0.0080

Polyphen

0.35

Vest4

0.19

MutPred

0.36

Gain of ubiquitination at E24 (P = 0.0198);

MVP

0.43

ClinPred

0.95

GERP RS

4.1

PromoterAI

0.022

Neutral

(source)

Varity_R

0.44

gMVP

0.61

Mutation Taster

=78/22

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.

17-74923004-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