Variant 3-44447500-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_181489.6(ZNF445):c.2171T>C(p.Phe724Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZNF445
NM_181489.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.877

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 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=0.33341658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF445	NM_181489.6 link	c.2171T>C	p.Phe724Ser	missense_variant	8/8	ENST00000396077.8	NP_852466.1	P59923
ZNF445	NM_001369454.1 link	c.2135T>C	p.Phe712Ser	missense_variant	7/7		NP_001356383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF445	ENST00000396077.8 link	c.2171T>C	p.Phe724Ser	missense_variant	8/8	1	NM_181489.6	ENSP00000379387.2		P59923
ZNF445	ENST00000425708.6 link	c.2171T>C	p.Phe724Ser	missense_variant	6/6	1		ENSP00000413073.2		P59923

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251130

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The c.2171T>C (p.F724S) alteration is located in exon 8 (coding exon 6) of the ZNF445 gene. This alteration results from a T to C substitution at nucleotide position 2171, causing the phenylalanine (F) at amino acid position 724 to be replaced by a serine (S). 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

0.88

BayesDel_addAF

Benign

-0.0066

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.088

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.29

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.40

B;B

Vest4

0.35

MutPred

0.70

Loss of stability (P = 5e-04);Loss of stability (P = 5e-04);

MVP

0.71

MPC

0.46

ClinPred

0.56

GERP RS

-0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.25

gMVP

0.43

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

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