15-70667464-C-A

Position:

• chr15-70667464-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000322954.11(UACA):​c.3220G>T​(p.Asp1074Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,610,104 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (31 hom.)
• Consequence: UACA ENST00000322954.11 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.60

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045127273).
• BP6: Variant 15-70667464-C-A is Benign according to our data. Variant chr15-70667464-C-A is described in ClinVar as [Benign]. Clinvar id is 3055452.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1643/152264) while in subpopulation AFR AF= 0.0382 (1587/41546). AF 95% confidence interval is 0.0366. There are 26 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UACA	NM_018003.4	c.3220G>T	p.Asp1074Tyr	missense_variant	16/19	ENST00000322954.11	NP_060473.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UACA	ENST00000322954.11	c.3220G>T	p.Asp1074Tyr	missense_variant	16/19	1	NM_018003.4	ENSP00000314556	P1
UACA	ENST00000539319.5	c.2893G>T	p.Asp965Tyr	missense_variant	13/16	1		ENSP00000438667
UACA	ENST00000379983.6	c.3181G>T	p.Asp1061Tyr	missense_variant	16/19	5		ENSP00000369319
UACA	ENST00000560441.5	c.3175G>T	p.Asp1059Tyr	missense_variant	16/19	5		ENSP00000454018

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152146 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00290 AC: 717 AN: 247544 Hom.: 15 AF XY: 0.00208 AC XY: 279 AN XY: 133834

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000670

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00108 AC: 1578 AN: 1457840 Hom.: 31 Cov.: 31 AF XY: 0.000943 AC XY: 684 AN XY: 725294

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.0108 AC: 1643 AN: 152264 Hom.: 26 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74436

Gnomad4 AFR AF: 0.0382

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00179 Hom.: 6

Bravo AF: 0.0122

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0325 AC: 143

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

UACA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as 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	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	0.52	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.98	D;.;.;D
Vest4		0.34
MVP		0.46
MPC		0.50
ClinPred		0.018	T
GERP RS		6.0
Varity_R		0.31
gMVP		0.22

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: rs61729919; hg19: chr15-70959803;