12-79689896-C-A

Variant names:

• chr12-79689896-C-A
• rs200630820
• NM_002583.4:c.349G>T

Variant summary

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

The NM_002583.4(PAWR):​c.349G>T​(p.Ala117Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,356,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A117T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PAWR NM_002583.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 0 publications found

Genes affected

PAWR (HGNC:8614): (pro-apoptotic WT1 regulator) This gene encodes a tumor suppressor protein that selectively induces apoptosis in cancer cells through intracellular and extracellular mechanisms. The intracellular mechanism involves the inhibition of pro-survival pathways and the activation of Fas-mediated apoptosis, while the extracellular mechanism involves the binding of a secreted form of this protein to glucose regulated protein 78 (GRP78) on the cell surface, which leads to activation of the extrinsic apoptotic pathway. This gene is located on the unstable human chromosomal 12q21 region and is often deleted or mutated different tumors. The encoded protein also plays an important role in the progression of age-related diseases. [provided by RefSeq, Aug 2017]

PPP1R12A-AS2 (HGNC:55456): (PPP1R12A antisense RNA 2)

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=0.06834775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002583.4. 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
	PAWR	NM_002583.4	MANE Select	c.349G>T	p.Ala117Ser	missense	Exon 2 of 7	NP_002574.2	Q96IZ0
	PAWR	NM_001354732.2		c.349G>T	p.Ala117Ser	missense	Exon 2 of 7	NP_001341661.1	Q96IZ0
	PAWR	NM_001354733.2		c.349G>T	p.Ala117Ser	missense	Exon 2 of 5	NP_001341662.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAWR	ENST00000328827.9	TSL:1 MANE Select	c.349G>T	p.Ala117Ser	missense	Exon 2 of 7	ENSP00000328088.4	Q96IZ0
	PAWR	ENST00000903360.1		c.349G>T	p.Ala117Ser	missense	Exon 1 of 6	ENSP00000573419.1
	PAWR	ENST00000912080.1		c.349G>T	p.Ala117Ser	missense	Exon 2 of 7	ENSP00000582139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1356270 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 667274

African (AFR) AF: 0.00 AC: 0 AN: 27864

American (AMR) AF: 0.00 AC: 0 AN: 31982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22882

East Asian (EAS) AF: 0.00 AC: 0 AN: 31914

South Asian (SAS) AF: 0.00 AC: 0 AN: 74244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4586

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1061344

Other (OTH) AF: 0.00 AC: 0 AN: 55990

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.90
DANN	Benign	0.72
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.55
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.020
Sift	Benign	0.48	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.24		Gain of catalytic residue at P121 (P = 8e-04)
MVP		0.13
MPC		0.39
ClinPred		0.051	T
GERP RS		0.37
PromoterAI		0.035	Neutral
Varity_R		0.024
gMVP		0.074
Mutation Taster		=98/2	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: rs200630820; hg19: chr12-80083676;