15-70669310-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_018003.4(UACA):c.1374A>C(p.Gln458His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,134 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

UACA
NM_018003.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.672

Variant links:

Genes affected

UACA (HGNC:15947): (uveal autoantigen with coiled-coil domains and ankyrin repeats) This gene encodes a protein that contains ankyrin repeats and coiled coil domains and likely plays a role in apoptosis. Studies in rodents have implicated the encoded protein in the stimulation of apoptosis and the regulation of mammary gland involution, in which the mammary gland returns to its pre-pregnant state. This protein has also been proposed to negatively regulate apoptosis based on experiments in human cell lines in which the protein was shown to interact with PRKC apoptosis WT1 regulator protein, also known as PAR-4, and inhibit translocation of the PAR-4 receptor. Autoantibodies to this protein have been identified in human patients with panuveitis and Graves' disease. Differential expression of this gene has been observed in various human cancers. [provided by RefSeq, May 2017]

UACA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034577549).

BP6

Variant 15-70669310-T-G is Benign according to our data. Variant chr15-70669310-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 437187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-70669310-T-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UACA	NM_018003.4 link	c.1374A>C	p.Gln458His	missense_variant	Exon 16 of 19	ENST00000322954.11	NP_060473.2	Q9BZF9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UACA	ENST00000322954.11 link	c.1374A>C	p.Gln458His	missense_variant	Exon 16 of 19	1	NM_018003.4	ENSP00000314556.6		Q9BZF9-1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

346

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00197

AC:

495

AN:

250886

Hom.:

AF XY:

0.00201

AC XY:

272

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00305

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00322

AC:

4705

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

2323

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00152

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00376

Gnomad4 OTH exome

AF:

0.00325

GnomAD4 genome

AF:

0.00227

AC:

346

AN:

152324

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00372

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00260

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00188

AC:

228

Asia WGS

AF:

0.000578

AC:

AN:

3474

EpiCase

AF:

0.00344

EpiControl

AF:

0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 16, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

UACA-related disorder

Benign:1

Sep 29, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;T;.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.86

D;D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.0035

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.2

M;.;.;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;.

Polyphen

0.98

D;.;.;D;.

Vest4

0.33

MutPred

0.063

Loss of ubiquitination at K462 (P = 0.0561);.;.;.;.;

MVP

0.27

MPC

0.46

ClinPred

0.044

GERP RS

-3.1

Varity_R

0.11

gMVP

0.38

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