12-107710505-C-G

Variant names:

• chr12-107710505-C-G
• rs533485700
• NM_007062.3:c.1391C>G

Variant summary

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

The NM_007062.3(PWP1):​c.1391C>G​(p.Ser464Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,558,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S464F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PWP1 NM_007062.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38
• Publications: 0 publications found

Genes affected

PWP1 (HGNC:17015): (PWP1 homolog, endonuclein) The protein encoded by this gene contains several WD-40 repeats and is found mostly in the nucleus. The expression and localization of this protein are cell cycle dependent. Expression of this gene is upregulated in pancreatic adenocarcinoma. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007062.3. 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
	PWP1	NM_007062.3	MANE Select	c.1391C>G	p.Ser464Cys	missense	Exon 14 of 15	NP_008993.1	Q13610-1
	PWP1	NM_001317962.2		c.1205C>G	p.Ser402Cys	missense	Exon 14 of 15	NP_001304891.1	B4DJV5
	PWP1	NM_001317963.2		c.755C>G	p.Ser252Cys	missense	Exon 14 of 15	NP_001304892.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PWP1	ENST00000412830.8	TSL:1 MANE Select	c.1391C>G	p.Ser464Cys	missense	Exon 14 of 15	ENSP00000387365.3	Q13610-1
	PWP1	ENST00000920794.1		c.1460C>G	p.Ser487Cys	missense	Exon 15 of 16	ENSP00000590853.1
	PWP1	ENST00000920793.1		c.1382C>G	p.Ser461Cys	missense	Exon 14 of 15	ENSP00000590852.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147606 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1411028 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 701744

African (AFR) AF: 0.0000312 AC: 1 AN: 32010

American (AMR) AF: 0.00 AC: 0 AN: 43276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23918

East Asian (EAS) AF: 0.00 AC: 0 AN: 37032

South Asian (SAS) AF: 0.00 AC: 0 AN: 85528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078700

Other (OTH) AF: 0.00 AC: 0 AN: 56776

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147606 Hom.: 0 Cov.: 30 AF XY: 0.0000140 AC XY: 1 AN XY: 71580

African (AFR) AF: 0.0000500 AC: 2 AN: 40018

American (AMR) AF: 0.00 AC: 0 AN: 14446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4964

South Asian (SAS) AF: 0.00 AC: 0 AN: 4588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67372

Other (OTH) AF: 0.00 AC: 0 AN: 2032

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.23
Sift	Benign	0.033	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.53
MutPred		0.48		Loss of disorder (P = 0.0292)
MVP		0.91
MPC		0.78
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.31
Mutation Taster		=64/36	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: rs533485700; hg19: chr12-108104282;