rs187043152

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

2
5
12

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

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
ZFPM2NM_012082.4 linkc.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
ZFPM2ENST00000407775.7 linkc.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.:
1
Cov.:
32
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.:
3
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.:
17
Cov.:
31
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.:
1
Cov.:
32
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.:
1
Bravo
AF:
0.00305
TwinsUK
AF:
0.00566
AC:
21
ALSPAC
AF:
0.00493
AC:
19
ESP6500AA
AF:
0.000259
AC:
1
ESP6500EA
AF:
0.00498
AC:
41
ExAC
AF:
0.00343
AC:
414
Asia WGS
AF:
0.000289
AC:
1
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
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 04, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:1
Jan 19, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ZFPM2: BS1, BS2 -

Apr 27, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tetralogy of Fallot Pathogenic:1
Jul 15, 2014
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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
Dec 04, 2019
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
0.23
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
22
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
D
LIST_S2
Uncertain
0.88
D;.;D
M_CAP
Uncertain
0.092
D
MetaRNN
Benign
0.012
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L;.;.
PrimateAI
Pathogenic
0.85
D
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
T
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.

Other links and lift over

dbSNP: rs187043152; hg19: chr8-106813942; API