12-79689914-C-G

Variant names:

• chr12-79689914-C-G
• rs994771459
• NM_002583.4:c.331G>C

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.331G>C​(p.Glu111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,286,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. E111K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: PAWR NM_002583.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.494
• 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=0.1760895).

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.331G>C	p.Glu111Gln	missense	Exon 2 of 7	NP_002574.2	Q96IZ0
	PAWR	NM_001354732.2		c.331G>C	p.Glu111Gln	missense	Exon 2 of 7	NP_001341661.1	Q96IZ0
	PAWR	NM_001354733.2		c.331G>C	p.Glu111Gln	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.331G>C	p.Glu111Gln	missense	Exon 2 of 7	ENSP00000328088.4	Q96IZ0
	PAWR	ENST00000903360.1		c.331G>C	p.Glu111Gln	missense	Exon 1 of 6	ENSP00000573419.1
	PAWR	ENST00000912080.1		c.331G>C	p.Glu111Gln	missense	Exon 2 of 7	ENSP00000582139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000311 AC: 4 AN: 1286578 Hom.: 0 Cov.: 32 AF XY: 0.00000318 AC XY: 2 AN XY: 628560

African (AFR) AF: 0.00 AC: 0 AN: 25176

American (AMR) AF: 0.00 AC: 0 AN: 19416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19282

East Asian (EAS) AF: 0.00 AC: 0 AN: 29020

South Asian (SAS) AF: 0.00 AC: 0 AN: 63732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4002

European-Non Finnish (NFE) AF: 0.00000387 AC: 4 AN: 1032812

Other (OTH) AF: 0.00 AC: 0 AN: 52996

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	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.096
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.49
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.043
Sift	Benign	0.21	T
Sift4G	Benign	0.56	T
Polyphen		0.87	P
Vest4		0.087
MutPred		0.18		Gain of catalytic residue at P112 (P = 0.0016)
MVP		0.28
MPC		1.1
ClinPred		0.73	D
GERP RS		3.3
PromoterAI		0.064	Neutral
Varity_R		0.19
gMVP		0.13
Mutation Taster		=95/5	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: rs994771459; hg19: chr12-80083694;