8-105419192-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012082.4(ZFPM2):c.89A>G(p.Glu30Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00419 in 1,613,668 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 16 hom. )

Consequence

ZFPM2
NM_012082.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:3B:9

Conservation

PhyloP100: 7.00

Variant links:

Genes affected

ZFPM2 (HGNC:16700): (zinc finger protein, FOG family member 2) The zinc finger protein encoded by this gene is a widely expressed member of the FOG family of transcription factors. The family members modulate the activity of GATA family proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals. It has been demonstrated that the protein can both activate and down-regulate expression of GATA-target genes, suggesting different modulation in different promoter contexts. A related mRNA suggests an alternatively spliced product but this information is not yet fully supported by the sequence. [provided by RefSeq, Jul 2008]

ZFPM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037163347).

BP6

Variant 8-105419192-A-G is Benign according to our data. Variant chr8-105419192-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 6128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-105419192-A-G is described in Lovd as [Likely_pathogenic]. Variant chr8-105419192-A-G is described in Lovd as [Likely_benign]. Variant chr8-105419192-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (452/152316) while in subpopulation NFE AF= 0.00529 (360/68008). AF 95% confidence interval is 0.00484. There are 2 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFPM2	NM_012082.4 link	c.89A>G	p.Glu30Gly	missense_variant	Exon 2 of 8	ENST00000407775.7	NP_036214.2	Q8WW38-1Q9NPQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFPM2	ENST00000407775.7 link	c.89A>G	p.Glu30Gly	missense_variant	Exon 2 of 8	1	NM_012082.4	ENSP00000384179.2		Q8WW38-1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

452

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00529

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00269

AC:

669

AN:

248808

Hom.:

AF XY:

0.00274

AC XY:

370

AN XY:

134990

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.00279

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00463

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00432

AC:

6315

AN:

1461352

Hom.:

Cov.:

AF XY:

0.00425

AC XY:

3088

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00142

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.00516

Gnomad4 OTH exome

AF:

0.00431

GnomAD4 genome

AF:

0.00297

AC:

452

AN:

152316

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00529

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00438

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00162

AC:

ESP6500EA

AF:

0.00584

AC:

ExAC

AF:

0.00270

AC:

326

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:3Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ZFPM2: BP4, BS1, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Nov 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ZFPM2 c.89A>G (p.Glu30Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 1613668 control chromosomes in the gnomAD database, including 18 homozygotes. The variant allele was found at a frequency of 0.0042 in 1613668 control chromosomes, predominantly at a frequency of 0.0052 within the Non-Finnish European subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2500-fold of the estimated maximal expected allele frequency for a pathogenic variant in ZFPM2 causing Tetralogy Of Fallot phenotype (2.1e-06), strongly suggesting the variant is a benign polymorphism. c.89A>G has been reported in the literature in control individuals and in individuals affected with Tetralogy Of Fallot or with atrioventricular septal defect, both without evidence of causality (e.g. D'Alessandro_2018, Pizzuti_2003, Priest_2016, Freudenberg-Hua_2014). These reports do not provide unequivocal conclusions about association of the variant with Tetralogy Of Fallot. At least one publication reports experimental evidence evaluating an impact on protein function, showing no damaging effect of this variant evidenced by maintained binding with and transcriptional activity of co-regulator of transcription, GATA4 (e.g. Pizzuti_2003). The following publications have been ascertained in the context of this evaluation (PMID: 25996639, 14517948, 27058611, 25333069). ClinVar contains an entry for this variant (Variation ID: 6128). Based on the evidence outlined above, the variant was classified as benign. -

Aug 08, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diaphragmatic hernia 3

Pathogenic:1

Apr 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Double outlet right ventricle

Pathogenic:1

Apr 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Tetralogy of Fallot

Pathogenic:1

Apr 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

46,XY sex reversal 9

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

46,XY sex reversal 3

Benign:1

Aug 26, 2019

Reproductive Development, Murdoch Childrens Research Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

ZFPM2-related disorder

Benign:1

Aug 16, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.59

M_CAP

Benign

0.031

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.33

Sift

Uncertain

0.011

Sift4G

Uncertain

0.054

Polyphen

0.89

Vest4

0.86

MVP

0.73

MPC

0.35

ClinPred

0.013

GERP RS

5.4

Varity_R

0.13

gMVP

0.29

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