NM_007062.3:c.1319C>T

Variant names:

• chr12-107710433-C-T
• NM_007062.3:c.1319C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_007062.3(PWP1):​c.1319C>T​(p.Pro440Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PWP1 NM_007062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

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.1319C>T	p.Pro440Leu	missense	Exon 14 of 15	NP_008993.1	Q13610-1
	PWP1	NM_001317962.2		c.1133C>T	p.Pro378Leu	missense	Exon 14 of 15	NP_001304891.1	B4DJV5
	PWP1	NM_001317963.2		c.683C>T	p.Pro228Leu	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.1319C>T	p.Pro440Leu	missense	Exon 14 of 15	ENSP00000387365.3	Q13610-1
	PWP1	ENST00000920794.1		c.1388C>T	p.Pro463Leu	missense	Exon 15 of 16	ENSP00000590853.1
	PWP1	ENST00000920793.1		c.1310C>T	p.Pro437Leu	missense	Exon 14 of 15	ENSP00000590852.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111592

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.59		Gain of sheet (P = 0.1208)
MVP		0.70
MPC		0.50
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.73
Mutation Taster		=24/76	disease causing

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

hg19: chr12-108104210;