chr8-105802189-A-C

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.2107A>C(p.Met703Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000175 in 1,613,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ZFPM2
NM_012082.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:5

Conservation

PhyloP100: 6.28

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:

ZFPM2-AS1 (HGNC:50698): (ZFPM2 antisense RNA 1)

ZFPM2-AS1 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=0.01158455).

BP6

Variant 8-105802189-A-C is Benign according to our data. Variant chr8-105802189-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 6130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000223 (34/152216) while in subpopulation EAS AF= 0.00601 (31/5162). AF 95% confidence interval is 0.00435. There are 1 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFPM2	NM_012082.4 link	c.2107A>C	p.Met703Leu	missense_variant	Exon 8 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.2107A>C	p.Met703Leu	missense_variant	Exon 8 of 8	1	NM_012082.4	ENSP00000384179.2		Q8WW38-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00599

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000495

AC:

123

AN:

248720

Hom.:

AF XY:

0.000467

AC XY:

AN XY:

134930

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00669

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1461650

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00486

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000223

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00601

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000257

ExAC

AF:

0.000405

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Diaphragmatic hernia 3

Pathogenic:1Uncertain:1

Nov 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

ZFPM2 is also known as FOG2. NM_012082.3:c.2107A>C in the ZFPM2 gene has an allele frequency of 0.007 in East Asian subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationTaster and PrimateAI. We interpret it as variant of uncertain significance (VUS). This variant was reported in a patient with a left-sided Congenital diaphragmatic hernia (PMID: 17568391). Tan et al reported that a patient with double outlet right ventricle harbors c.2107A>C and proven to be de novo (PMID: 21919901). Taken together, we interprete this variant as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM6; PP3. -

Double outlet right ventricle

Pathogenic:1

Nov 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Tetralogy of Fallot;C1857781:Diaphragmatic hernia 3;C4015129:46,XY sex reversal 9

Uncertain:1

Sep 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:1

Aug 19, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

46,XY sex reversal 9

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

Mar 20, 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

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

T;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.55

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.091

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.93

P;.;.

Vest4

0.78

MutPred

0.32

Gain of catalytic residue at M703 (P = 0.0165);.;.;

MVP

0.52

MPC

0.20

ClinPred

0.12

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.38

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