18-59902683-T-C

Variant names:

• chr18-59902683-T-C
• rs754253425
• NM_021127.3:c.95T>C

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.95T>C​(p.Phe32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. F32C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PMAIP1 NM_021127.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.62
• 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=0.13263762).

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.95T>C	p.Phe32Ser	missense	Exon 2 of 2	NP_066950.1	A0A0S2Z490
	PMAIP1	NM_001382615.1		c.113T>C	p.Phe38Ser	missense	Exon 3 of 3	NP_001369544.1
	PMAIP1	NM_001382616.1		c.246T>C	p.Ile82Ile	synonymous	Exon 3 of 3	NP_001369545.1	Q13794-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMAIP1	ENST00000316660.7	TSL:1 MANE Select	c.95T>C	p.Phe32Ser	missense	Exon 2 of 2	ENSP00000326119.7	Q13794-1
	PMAIP1	ENST00000269518.9	TSL:1	c.246T>C	p.Ile82Ile	synonymous	Exon 3 of 3	ENSP00000269518.9	Q13794-2
	PMAIP1	ENST00000919087.1		c.95T>C	p.Phe32Ser	missense	Exon 3 of 3	ENSP00000589146.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251382 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.052
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0	B
Vest4		0.30
MutPred		0.33		Gain of relative solvent accessibility (P = 0.0104)
MVP		0.32
MPC		0.32
ClinPred		0.57	D
GERP RS		2.7
Varity_R		0.44
gMVP		0.21
Mutation Taster		=89/11	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: rs754253425; hg19: chr18-57569915;