rs187043152

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_012082.4(ZFPM2):c.1632G>A(p.Met544Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,784 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 17 hom. )

Consequence

ZFPM2
NM_012082.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:7

Conservation

PhyloP100: 8.00

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:

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011999905).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00344 (524/152200) while in subpopulation NFE AF= 0.00516 (351/67996). AF 95% confidence interval is 0.00472. There are 1 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFPM2	NM_012082.4 link	c.1632G>A	p.Met544Ile	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.1632G>A	p.Met544Ile	missense_variant	Exon 8 of 8	1	NM_012082.4	ENSP00000384179.2		Q8WW38-1

Frequencies

GnomAD3 genomes

AF:

0.00345

AC:

524

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00516

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00338

AC:

837

AN:

247958

Hom.:

AF XY:

0.00329

AC XY:

443

AN XY:

134660

show subpopulations

Gnomad AFR exome

AF:

0.000520

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00348

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00545

Gnomad NFE exome

AF:

0.00487

Gnomad OTH exome

AF:

0.00298

GnomAD4 exome

AF:

0.00460

AC:

6722

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3174

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00248

Gnomad4 ASJ exome

AF:

0.00318

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00475

Gnomad4 NFE exome

AF:

0.00531

Gnomad4 OTH exome

AF:

0.00484

GnomAD4 genome

AF:

0.00344

AC:

524

AN:

152200

Hom.:

Cov.:

AF XY:

0.00331

AC XY:

246

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.00516

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00415

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00498

AC:

ExAC

AF:

0.00343

AC:

414

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00518

EpiControl

AF:

0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

46,XY sex reversal 9

Pathogenic:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2025	- -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in a sporadic case with TOF (De Luca 2011), one homozygous case with 46,XY gonadal dysgenesis (Bashamboo 2014), one case with congenital diaphragmatic hernia and was inherited from the mother (Longoni 2015). ExAC freq 0.5%. -

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ZFPM2: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

Tetralogy of Fallot

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2014

- -

46,XY sex reversal 3

Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

ZFPM2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

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

0.23

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.90

N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.28

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.14

B;.;.

Vest4

0.64

MutPred

0.32

Loss of solvent accessibility (P = 0.0352);.;.;

MVP

0.45

MPC

0.14

ClinPred

0.022

GERP RS

6.0

Varity_R

0.37

gMVP

0.37

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