18-59902724-A-C

Variant names:

• chr18-59902724-A-C
• NM_021127.3:c.136A>C
• PMAIP1 p.Ile46Leu

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.136A>C​(p.Ile46Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMAIP1 NM_021127.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• 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]

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=0.096609294).

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.136A>C	p.Ile46Leu	missense	Exon 2 of 2	NP_066950.1	A0A0S2Z490
	PMAIP1	NM_001382616.1		c.287A>C	p.Asp96Ala	missense	Exon 3 of 3	NP_001369545.1	Q13794-2
	PMAIP1	NM_001382618.1		c.281A>C	p.Asp94Ala	missense	Exon 3 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.136A>C	p.Ile46Leu	missense	Exon 2 of 2	ENSP00000326119.7	Q13794-1
	PMAIP1	ENST00000269518.9	TSL:1	c.287A>C	p.Asp96Ala	missense	Exon 3 of 3	ENSP00000269518.9	Q13794-2
	PMAIP1	ENST00000919087.1		c.136A>C	p.Ile46Leu	missense	Exon 3 of 3	ENSP00000589146.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.92
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.032
Sift4G	Pathogenic	0.0	D
Varity_R		0.10
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-57569956;