15-70669310-T-G

Variant names:

• chr15-70669310-T-G
• rs78821209
• NM_018003.4:c.1374A>C

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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:3
• Conservation: PhyloP100: -0.672
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 437187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018003.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UACA	NM_018003.4	MANE Select	c.1374A>C	p.Gln458His	missense	Exon 16 of 19	NP_060473.2	Q9BZF9-1
	UACA	NM_001008224.3		c.1335A>C	p.Gln445His	missense	Exon 16 of 19	NP_001008225.1	Q9BZF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UACA	ENST00000322954.11	TSL:1 MANE Select	c.1374A>C	p.Gln458His	missense	Exon 16 of 19	ENSP00000314556.6	Q9BZF9-1
	UACA	ENST00000539319.5	TSL:1	c.1047A>C	p.Gln349His	missense	Exon 13 of 16	ENSP00000438667.1	F5H2B9
	UACA	ENST00000558758.5	TSL:1	c.1302A>C	p.Gln434His	missense	Exon 15 of 15	ENSP00000453865.1	H0YN48

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

GnomAD2 exomes AF: 0.00197 AC: 495 AN: 250886 AF XY: 0.00201

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 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

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.000961 AC: 43 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00152 AC: 131 AN: 86254

European-Finnish (FIN) AF: 0.00223 AC: 119 AN: 53414

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00376 AC: 4186 AN: 1111956

Other (OTH) AF: 0.00325 AC: 196 AN: 60394

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74496

African (AFR) AF: 0.000649 AC: 27 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00372 AC: 253 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00268 Hom.: 6

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	UACA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.67
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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