15-70669310-T-G

Position:

• chr15-70669310-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.672

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]

ACMG classification

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/exons	MANE	UniProt
UACA	NM_018003.4	c.1374A>C	p.Gln458His	missense_variant	16/19	ENST00000322954.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UACA	ENST00000322954.11	c.1374A>C	p.Gln458His	missense_variant	16/19	1	NM_018003.4	P1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152206 Hom.: 1 Cov.: 32

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.: 3 AF XY: 0.00201 AC XY: 272 AN XY: 135564

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.: 11 Cov.: 35 AF XY: 0.00319 AC XY: 2323 AN XY: 727210

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.: 1 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74496

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.: 2

Bravo AF: 0.00220

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.000578 AC: 2 AN: 3474

EpiCase AF: 0.00344

EpiControl AF: 0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 16, 2016

- -

UACA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
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	N
LIST_S2	Benign	0.86	D;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
MutationTaster	Benign	0.83	D;D;D;D
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs78821209; hg19: chr15-70961649; COSMIC: COSV100537209; COSMIC: COSV100537209;