3-44446720-C-T

Position:

• chr3-44446720-C-T

Variant summary

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

The NM_181489.6(ZNF445):​c.2951G>A​(p.Gly984Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: ZNF445 NM_181489.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

Genes affected

ZNF445 (HGNC:21018): (zinc finger protein 445) Enables double-stranded methylated DNA binding activity. Involved in maintenance of DNA methylation and regulation of genetic imprinting. Located 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
ZNF445	NM_181489.6	c.2951G>A	p.Gly984Glu	missense_variant	8/8	ENST00000396077.8	NP_852466.1
ZNF445	NM_001369454.1	c.2915G>A	p.Gly972Glu	missense_variant	7/7		NP_001356383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF445	ENST00000396077.8	c.2951G>A	p.Gly984Glu	missense_variant	8/8	1	NM_181489.6	ENSP00000379387	P1
ZNF445	ENST00000425708.6	c.2951G>A	p.Gly984Glu	missense_variant	6/6	1		ENSP00000413073	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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 13, 2023

The c.2951G>A (p.G984E) alteration is located in exon 8 (coding exon 6) of the ZNF445 gene. This alteration results from a G to A substitution at nucleotide position 2951, causing the glycine (G) at amino acid position 984 to be replaced by a glutamic acid (E). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.90	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.17
Sift	Benign	0.066	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;D
Vest4		0.51
MutPred		0.63		Loss of MoRF binding (P = 0.0253);Loss of MoRF binding (P = 0.0253);
MVP		0.54
MPC		1.0
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr3-44488212;