Genetic Variant NM_181489.6:c.2462A>G (chr3-44447209-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181489.6(ZNF445):c.2462A>G(p.His821Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF445
NM_181489.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.09

Variant links:

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]

ZNF445 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03410688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF445	NM_181489.6 link	c.2462A>G	p.His821Arg	missense_variant	Exon 8 of 8	ENST00000396077.8	NP_852466.1	P59923
ZNF445	NM_001369454.1 link	c.2426A>G	p.His809Arg	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 link	c.2462A>G	p.His821Arg	missense_variant	Exon 8 of 8	1	NM_181489.6	ENSP00000379387.2		P59923
ZNF445	ENST00000425708.6 link	c.2462A>G	p.His821Arg	missense_variant	Exon 6 of 6	1		ENSP00000413073.2		P59923

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250640

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2462A>G (p.H821R) 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 2462, causing the histidine (H) at amino acid position 821 to be replaced by an arginine (R). 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

0.073

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0030

DANN

Benign

0.48

DEOGEN2

Benign

0.0062

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0026

M_CAP

Benign

0.0035

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.15

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.020

Sift

Benign

0.39

T;T

Sift4G

Benign

0.67

T;T

Polyphen

0.0

B;B

Vest4

0.062

MutPred

0.20

Gain of glycosylation at Y818 (P = 0.0049);Gain of glycosylation at Y818 (P = 0.0049);

MVP

0.17

MPC

0.31

ClinPred

0.029

GERP RS

-6.8

Varity_R

0.021

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over