Genetic Variant UACA:p.Val1223Val (chr15-70667015-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_018003.4(UACA):c.3669A>G(p.Val1223Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,470 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

UACA
NM_018003.4 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.918

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 15-70667015-T-C is Benign according to our data. Variant chr15-70667015-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3040009.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.918 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UACA	NM_018003.4 link	c.3669A>G	p.Val1223Val	synonymous_variant	Exon 16 of 19	ENST00000322954.11	NP_060473.2	Q9BZF9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UACA	ENST00000322954.11 link	c.3669A>G	p.Val1223Val	synonymous_variant	Exon 16 of 19	1	NM_018003.4	ENSP00000314556.6	Q9BZF9-1
UACA	ENST00000539319.5 link	c.3342A>G	p.Val1114Val	synonymous_variant	Exon 13 of 16	1		ENSP00000438667.1	F5H2B9
UACA	ENST00000379983.6 link	c.3630A>G	p.Val1210Val	synonymous_variant	Exon 16 of 19	5		ENSP00000369319.2	Q9BZF9-2
UACA	ENST00000560441.5 link	c.3624A>G	p.Val1208Val	synonymous_variant	Exon 16 of 19	5		ENSP00000454018.1	H0YNH8

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

271

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

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:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000451

AC:

113

AN:

250306

Hom.:

AF XY:

0.000362

AC XY:

AN XY:

135316

show subpopulations

Gnomad AFR exome

AF:

0.00617

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1461142

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.00446

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.00179

AC:

272

AN:

152328

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00531

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000770

Hom.:

Bravo

AF:

0.00201

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

UACA-related disorder

Benign:1

Oct 28, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.25

DANN

Benign

0.64

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