3-28524594-T-C

Position:

• chr3-28524594-T-C

Variant summary

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

The NM_001040432.4(ZCWPW2):​c.977T>C​(p.Leu326Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.45

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZCWPW2	NM_001040432.4	c.977T>C	p.Leu326Pro	missense_variant	10/10	ENST00000383768.7	NP_001035522.1
ZCWPW2	NM_001324169.2	c.977T>C	p.Leu326Pro	missense_variant	9/9		NP_001311098.1
ZCWPW2	NM_001324170.2	c.791T>C	p.Leu264Pro	missense_variant	7/7		NP_001311099.1
ZCWPW2	NR_136708.2	n.1355T>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCWPW2	ENST00000383768.7	c.977T>C	p.Leu326Pro	missense_variant	10/10	1	NM_001040432.4	ENSP00000373278	P1
ZCWPW2	ENST00000419130.5	c.632T>C	p.Leu211Pro	missense_variant	8/8	1		ENSP00000395687
ZCWPW2	ENST00000457897.1	c.377+3478T>C		intron_variant		5		ENSP00000395421

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247612 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome Cov.: 30

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

Oct 06, 2022

The c.977T>C (p.L326P) alteration is located in exon 9 (coding exon 8) of the ZCWPW2 gene. This alteration results from a T to C substitution at nucleotide position 977, causing the leucine (L) at amino acid position 326 to be replaced by a proline (P). 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	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.40		Loss of sheet (P = 0.0025);
MVP		0.47
MPC		0.15
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.49
gMVP		0.73

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: rs1455403579; hg19: chr3-28566085;