3-44447458-T-C

Variant names:

• chr3-44447458-T-C
• NM_181489.6:c.2213A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181489.6(ZNF445):​c.2213A>G​(p.Glu738Gly) 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. 13/21 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: ZNF445 NM_181489.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.225

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09172174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF445	NM_181489.6	c.2213A>G	p.Glu738Gly	missense_variant	Exon 8 of 8	ENST00000396077.8	NP_852466.1
ZNF445	NM_001369454.1	c.2177A>G	p.Glu726Gly	missense_variant	Exon 7 of 7		NP_001356383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF445	ENST00000396077.8	c.2213A>G	p.Glu738Gly	missense_variant	Exon 8 of 8	1	NM_181489.6	ENSP00000379387.2
ZNF445	ENST00000425708.6	c.2213A>G	p.Glu738Gly	missense_variant	Exon 6 of 6	1		ENSP00000413073.2

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

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2213A>G (p.E738G) alteration is located in exon 8 (coding exon 6) of the ZNF445 gene. This alteration results from a A to G substitution at nucleotide position 2213, causing the glutamic acid (E) at amino acid position 738 to be replaced by a glycine (G). 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	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.054	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.088
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.16	B;B
Vest4		0.21
MutPred		0.28		Loss of solvent accessibility (P = 0.0187);Loss of solvent accessibility (P = 0.0187);
MVP		0.17
MPC		0.30
ClinPred		0.45	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.15

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: chr3-44488950;