Variant 3-28520994-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040432.4(ZCWPW2):c.787G>A(p.Val263Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZCWPW2
NM_001040432.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

ZCWPW2 (HGNC:23574): (zinc finger CW-type and PWWP domain containing 2) Enables methylated histone binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZCWPW2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06514794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZCWPW2	NM_001040432.4 linkuse as main transcript	c.787G>A	p.Val263Ile	missense_variant, splice_region_variant	9/10	ENST00000383768.7	NP_001035522.1
ZCWPW2	NM_001324169.2 linkuse as main transcript	c.787G>A	p.Val263Ile	missense_variant, splice_region_variant	8/9		NP_001311098.1
ZCWPW2	NM_001324170.2 linkuse as main transcript	c.601G>A	p.Val201Ile	missense_variant, splice_region_variant	6/7		NP_001311099.1
ZCWPW2	NR_136708.2 linkuse as main transcript	n.1165G>A		splice_region_variant, non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZCWPW2	ENST00000383768.7 linkuse as main transcript	c.787G>A	p.Val263Ile	missense_variant, splice_region_variant	9/10	1	NM_001040432.4	ENSP00000373278	P1
ZCWPW2	ENST00000419130.5 linkuse as main transcript	c.442G>A	p.Val148Ile	missense_variant, splice_region_variant	7/8	1		ENSP00000395687
ZCWPW2	ENST00000457897.1 linkuse as main transcript	c.256G>A	p.Val86Ile	missense_variant, splice_region_variant	4/6	5		ENSP00000395421

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250180

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460708

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726664

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000577

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The c.787G>A (p.V263I) alteration is located in exon 8 (coding exon 7) of the ZCWPW2 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the valine (V) at amino acid position 263 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0058

Eigen

Benign

-0.062

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.77

M_CAP

Benign

0.0087

MetaRNN

Benign

0.065

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.33

REVEL

Benign

0.032

Sift

Benign

0.18

Sift4G

Benign

0.23

Polyphen

0.40

Vest4

0.21

MutPred

0.21

Loss of helix (P = 0.0138);

MVP

0.095

MPC

0.094

ClinPred

0.68

GERP RS

4.6

Varity_R

0.049

gMVP

0.061

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over