4-271775-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001137608.3(ZNF732):c.1082C>T(p.Pro361Leu) 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. 12/21 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: ZNF732 NM_001137608.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

ZNF732 (HGNC:37138): (zinc finger protein 732) This gene encodes a kruppel-associated box-containing zinc finger protein (KRAB-ZFP). The encoded protein contains an N-terminal kruppel-associated box (KRAB) domain and sixteen C-terminal C2H2-type zinc finger domains. The KRAB-ZFPs represent the largest family of mammalian transcriptional repressors, which function through the recruitment of the nuclear co-factor KRAB-Associated Protein 1 (KAP1), to engage histone modifiers and induce heterochromatin formation. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35294044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF732	NM_001137608.3	c.1082C>T	p.Pro361Leu	missense_variant	4/4	ENST00000419098.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF732	ENST00000419098.6	c.1082C>T	p.Pro361Leu	missense_variant	4/4	2	NM_001137608.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Dec 20, 2021

The c.1082C>T (p.P361L) alteration is located in exon 4 (coding exon 4) of the ZNF732 gene. This alteration results from a C to T substitution at nucleotide position 1082, causing the proline (P) at amino acid position 361 to be replaced by a leucine (L). 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	0.71
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	13
Dann	Uncertain	0.99
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	.;D
Vest4		0.13
MutPred		0.45		.;Loss of catalytic residue at P361 (P = 0.0514);
MVP		0.26
MPC		0.025
ClinPred		0.98	D
GERP RS		0.98
Varity_R		0.088
gMVP		0.0096

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-265564; COSMIC: COSV69956761; COSMIC: COSV69956761;