12-107704676-C-T

Variant names:

• chr12-107704676-C-T
• NM_007062.3:c.1006C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007062.3(PWP1):​c.1006C>T​(p.His336Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PWP1 NM_007062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096372634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PWP1	NM_007062.3	c.1006C>T	p.His336Tyr	missense_variant	Exon 11 of 15	ENST00000412830.8	NP_008993.1
PWP1	NM_001317962.2	c.820C>T	p.His274Tyr	missense_variant	Exon 11 of 15		NP_001304891.1
PWP1	NM_001317963.2	c.370C>T	p.His124Tyr	missense_variant	Exon 11 of 15		NP_001304892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PWP1	ENST00000412830.8	c.1006C>T	p.His336Tyr	missense_variant	Exon 11 of 15	1	NM_007062.3	ENSP00000387365.3
PWP1	ENST00000541166.1	c.820C>T	p.His274Tyr	missense_variant	Exon 11 of 15	2		ENSP00000445249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1006C>T (p.H336Y) alteration is located in exon 11 (coding exon 11) of the PWP1 gene. This alteration results from a C to T substitution at nucleotide position 1006, causing the histidine (H) at amino acid position 336 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.0061	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;.
Vest4		0.33
MutPred		0.39		Loss of disorder (P = 0.0529);.;
MVP		0.25
MPC		0.32
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.038
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-108098453;