Variant 18-59900205-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021127.3(PMAIP1):c.28G>A(p.Ala10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,403,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PMAIP1
NM_021127.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.114

Variant links:

Genes affected

PMAIP1 (HGNC:9108): (phorbol-12-myristate-13-acetate-induced protein 1) This gene belongs to a pro-apoptotic subfamily within the BCL-2 protein family, referred to as the BCL-2 homology domain 3 (BH3)-only subfamily, which determine whether a cell commits to apoptosis. In response to death-inducing stimuli, BH3-only members inhibit the anti-apoptotic BCL-2 family members, which under steady-state conditions keep the multi-BH domain proteins BAX and BAK, in an inactive state. [provided by RefSeq, Aug 2020]

PMAIP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.064691156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMAIP1	NM_021127.3 linkuse as main transcript	c.28G>A	p.Ala10Thr	missense_variant	1/2	ENST00000316660.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMAIP1	ENST00000316660.7 linkuse as main transcript	c.28G>A	p.Ala10Thr	missense_variant	1/2	1	NM_021127.3	P1	Q13794-1
PMAIP1	ENST00000269518.9 linkuse as main transcript	c.28G>A	p.Ala10Thr	missense_variant	1/3	1			Q13794-2
PMAIP1	ENST00000590596.1 linkuse as main transcript	n.170G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000193

AC:

AN:

155306

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

84542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000401

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:

0.0000318

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1403950

Hom.:

Cov.:

AF XY:

0.00000577

AC XY:

AN XY:

693536

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000276

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000129

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000130

AC:

ExAC

AF:

0.0000189

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.28G>A (p.A10T) alteration is located in exon 1 (coding exon 1) of the PMAIP1 gene. This alteration results from a G to A substitution at nucleotide position 28, causing the alanine (A) at amino acid position 10 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

0.078

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.87

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.68

N;D

REVEL

Benign

0.036

Sift

Benign

0.47

T;.

Sift4G

Benign

0.46

T;.

Polyphen

0.31

B;.

Vest4

0.068

MVP

0.14

MPC

0.28

ClinPred

0.63

GERP RS

1.9

Varity_R

0.067

gMVP

0.012

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