3-28478869-G-T

Position:

• chr3-28478869-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040432.4(ZCWPW2):​c.548G>T​(p.Cys183Phe) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZCWPW2 NM_001040432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.312

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]

ACMG classification

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=0.037868112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCWPW2	NM_001040432.4	c.548G>T	p.Cys183Phe	missense_variant	5/10	ENST00000383768.7	NP_001035522.1
ZCWPW2	NM_001324169.2	c.548G>T	p.Cys183Phe	missense_variant	4/9		NP_001311098.1
ZCWPW2	NM_001324170.2	c.493-13258G>T		intron_variant			NP_001311099.1
ZCWPW2	NR_136708.2	n.989-13258G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCWPW2	ENST00000383768.7	c.548G>T	p.Cys183Phe	missense_variant	5/10	1	NM_001040432.4	ENSP00000373278	P1
ZCWPW2	ENST00000419130.5	c.203G>T	p.Cys68Phe	missense_variant	3/8	1		ENSP00000395687

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.548G>T (p.C183F) alteration is located in exon 4 (coding exon 3) of the ZCWPW2 gene. This alteration results from a G to T substitution at nucleotide position 548, causing the cysteine (C) at amino acid position 183 to be replaced by a phenylalanine (F). 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	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.026
DANN	Benign	0.36
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.071
Sift	Benign	0.67	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.24
MPC		0.021
ClinPred		0.019	T
GERP RS		1.2
Varity_R		0.054
gMVP		0.12

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

Other links and lift over

dbSNP: rs1315932434; hg19: chr3-28520360;