18-59900212-C-G

Variant names:

• chr18-59900212-C-G
• rs769494393
• NM_021127.3:c.35C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021127.3(PMAIP1):​c.35C>G​(p.Pro12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PMAIP1 NM_021127.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00100
• Publications: 0 publications found

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]

ENSG00000310295 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12234825).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021127.3. 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
	PMAIP1	NM_021127.3	MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 2	NP_066950.1	A0A0S2Z490
	PMAIP1	NM_001382616.1		c.35C>G	p.Pro12Arg	missense	Exon 1 of 3	NP_001369545.1	Q13794-2
	PMAIP1	NM_001382618.1		c.35C>G	p.Pro12Arg	missense	Exon 1 of 3	NP_001369547.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMAIP1	ENST00000316660.7	TSL:1 MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 2	ENSP00000326119.7	Q13794-1
	PMAIP1	ENST00000269518.9	TSL:1	c.35C>G	p.Pro12Arg	missense	Exon 1 of 3	ENSP00000269518.9	Q13794-2
	PMAIP1	ENST00000919087.1		c.35C>G	p.Pro12Arg	missense	Exon 2 of 3	ENSP00000589146.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402242 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692554

African (AFR) AF: 0.00 AC: 0 AN: 32546

American (AMR) AF: 0.00 AC: 0 AN: 36086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 37298

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084488

Other (OTH) AF: 0.00 AC: 0 AN: 58268

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.0010
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.036
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.033	D
Polyphen		0.86	P
Vest4		0.15
MutPred		0.13		Gain of MoRF binding (P = 0.0066)
MVP		0.20
MPC		0.46
ClinPred		0.82	D
GERP RS		1.9
PromoterAI		0.013	Neutral
Varity_R		0.15
gMVP		0.010
Mutation Taster		=99/1	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: rs769494393; hg19: chr18-57567444;