Variant 3-44446954-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000396077.8(ZNF445):c.2717T>C(p.Ile906Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

ZNF445
ENST00000396077.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.38

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:

Genome browser will be placed here

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=0.009923756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF445	NM_181489.6 linkuse as main transcript	c.2717T>C	p.Ile906Thr	missense_variant	8/8	ENST00000396077.8	NP_852466.1	P59923
ZNF445	NM_001369454.1 linkuse as main transcript	c.2681T>C	p.Ile894Thr	missense_variant	7/7		NP_001356383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF445	ENST00000396077.8 linkuse as main transcript	c.2717T>C	p.Ile906Thr	missense_variant	8/8	1	NM_181489.6	ENSP00000379387.2		P59923
ZNF445	ENST00000425708.6 linkuse as main transcript	c.2717T>C	p.Ile906Thr	missense_variant	6/6	1		ENSP00000413073.2		P59923

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251356

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

175

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000262

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000230

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

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

Oct 26, 2022

The c.2717T>C (p.I906T) 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 2717, causing the isoleucine (I) at amino acid position 906 to be replaced by a threonine (T). 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

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.14

DEOGEN2

Benign

0.0032

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.016

M_CAP

Benign

0.0064

MetaRNN

Benign

0.0099

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.99

N;N

REVEL

Benign

0.0070

Sift

Benign

0.77

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.064

B;B

Vest4

0.27

MVP

0.15

MPC

0.58

ClinPred

0.0027

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.12

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