15-70666926-T-G

Position:

• chr15-70666926-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018003.4(UACA):​c.3758A>C​(p.Lys1253Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000237 in 1,612,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: UACA NM_018003.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077677935).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UACA	NM_018003.4	c.3758A>C	p.Lys1253Thr	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.3758A>C	p.Lys1253Thr	missense_variant	16/19	1	NM_018003.4	ENSP00000314556	P1
UACA	ENST00000539319.5	c.3431A>C	p.Lys1144Thr	missense_variant	13/16	1		ENSP00000438667
UACA	ENST00000379983.6	c.3719A>C	p.Lys1240Thr	missense_variant	16/19	5		ENSP00000369319
UACA	ENST00000560441.5	c.3713A>C	p.Lys1238Thr	missense_variant	16/19	5		ENSP00000454018

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000352 AC: 88 AN: 249732 Hom.: 0 AF XY: 0.000319 AC XY: 43 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000786

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000233

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1460532 Hom.: 2 Cov.: 31 AF XY: 0.000251 AC XY: 182 AN XY: 726448

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000854

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74470

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.3758A>C (p.K1253T) alteration is located in exon 16 (coding exon 16) of the UACA gene. This alteration results from a A to C substitution at nucleotide position 3758, causing the lysine (K) at amino acid position 1253 to be replaced by a threonine (T). 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	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.078	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Benign	0.31	T;T;T;T
Polyphen		1.0	D;.;.;D
Vest4		0.38
MVP		0.66
MPC		0.28
ClinPred		0.14	T
GERP RS		5.7
Varity_R		0.38
gMVP		0.28

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: rs201992560; hg19: chr15-70959265;