4-271374-T-G

Variant names:

• chr4-271374-T-G
• rs782534382
• NM_001137608.3:c.1483A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001137608.3(ZNF732):​c.1483A>C​(p.Ile495Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I495V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ZNF732 NM_001137608.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.277
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10737184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137608.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF732	NM_001137608.3	MANE Select	c.1483A>C	p.Ile495Leu	missense	Exon 4 of 4	NP_001131080.1	B4DXR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF732	ENST00000419098.6	TSL:2 MANE Select	c.1483A>C	p.Ile495Leu	missense	Exon 4 of 4	ENSP00000415774.1	B4DXR9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447880 Hom.: 0 Cov.: 33 AF XY: 0.00000556 AC XY: 4 AN XY: 719336

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 41990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39024

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104844

Other (OTH) AF: 0.00 AC: 0 AN: 59934

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.28
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.024
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.37	B
Vest4		0.090
MutPred		0.44		Loss of methylation at K493 (P = 0.05)
MVP		0.014
MPC		0.0097
ClinPred		0.19	T
GERP RS		0.98
Varity_R		0.16
gMVP		0.0096
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs782534382; hg19: chr4-265163;