12-107708927-C-T

Variant names:

• chr12-107708927-C-T
• rs142592988
• NM_007062.3:c.1079C>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.1079C>T​(p.Ala360Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000246 in 1,612,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PWP1 NM_007062.3 missense, splice_region
• Scores: Splicing: ADA: 0.2644
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

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=0.10331884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PWP1	NM_007062.3	c.1079C>T	p.Ala360Val	missense_variant, splice_region_variant	Exon 12 of 15	ENST00000412830.8	NP_008993.1
PWP1	NM_001317962.2	c.893C>T	p.Ala298Val	missense_variant, splice_region_variant	Exon 12 of 15		NP_001304891.1
PWP1	NM_001317963.2	c.443C>T	p.Ala148Val	missense_variant, splice_region_variant	Exon 12 of 15		NP_001304892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PWP1	ENST00000412830.8	c.1079C>T	p.Ala360Val	missense_variant, splice_region_variant	Exon 12 of 15	1	NM_007062.3	ENSP00000387365.3
PWP1	ENST00000541166.1	c.893C>T	p.Ala298Val	missense_variant, splice_region_variant	Exon 12 of 15	2		ENSP00000445249.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 250868 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135592

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1460434 Hom.: 0 Cov.: 31 AF XY: 0.000233 AC XY: 169 AN XY: 726580

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000762

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1079C>T (p.A360V) alteration is located in exon 12 (coding exon 12) of the PWP1 gene. This alteration results from a C to T substitution at nucleotide position 1079, causing the alanine (A) at amino acid position 360 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0087	T;.
Eigen	Benign	-0.00064
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.13
Sift	Benign	0.62	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.58	P;.
Vest4		0.35
MVP		0.32
MPC		0.29
ClinPred		0.035	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.26
dbscSNV1_RF	Benign	0.53
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

Publications

LitVar

Other links and lift over

dbSNP: rs142592988; hg19: chr12-108102704;