8-105419192-A-G

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. E30E) has been classified 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

1
7
11

Clinical Significance

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

Conservation

PhyloP100: 7.00

Publications

19 publications found
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 Gene-Disease associations (from GenCC):
  • 46,XY sex reversal 9
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • diaphragmatic hernia 3
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • tetralogy of fallot
    Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • 46,XY partial gonadal dysgenesis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.
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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High AC in GnomAd4 at 452 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZFPM2NM_012082.4 linkc.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
ZFPM2ENST00000407775.7 linkc.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.:
2
Cov.:
32
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
GnomAD2 exomes
AF:
0.00269
AC:
669
AN:
248808
AF XY:
0.00274
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 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.:
16
Cov.:
31
AF XY:
0.00425
AC XY:
3088
AN XY:
726950
show subpopulations
African (AFR)
AF:
0.000538
AC:
18
AN:
33472
American (AMR)
AF:
0.000783
AC:
35
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00337
AC:
88
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.00142
AC:
122
AN:
86210
European-Finnish (FIN)
AF:
0.00107
AC:
57
AN:
53390
Middle Eastern (MID)
AF:
0.000347
AC:
2
AN:
5768
European-Non Finnish (NFE)
AF:
0.00516
AC:
5733
AN:
1111672
Other (OTH)
AF:
0.00431
AC:
260
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
314
627
941
1254
1568
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
190
380
570
760
950
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00297
AC:
452
AN:
152316
Hom.:
2
Cov.:
32
AF XY:
0.00277
AC XY:
206
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.000914
AC:
38
AN:
41590
American (AMR)
AF:
0.000588
AC:
9
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00317
AC:
11
AN:
3468
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5182
South Asian (SAS)
AF:
0.00269
AC:
13
AN:
4828
European-Finnish (FIN)
AF:
0.00179
AC:
19
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00529
AC:
360
AN:
68008
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
20
40
61
81
101
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00394
Hom.:
5
Bravo
AF:
0.00264
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00363
AC:
14
ESP6500AA
AF:
0.00162
AC:
6
ESP6500EA
AF:
0.00584
AC:
48
ExAC
AF:
0.00270
AC:
326
Asia WGS
AF:
0.00173
AC:
6
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
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ZFPM2: BP4, BS1, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:2
Aug 08, 2017
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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. -

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
T
BayesDel_noAF
Uncertain
0.010
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.59
T
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.037
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
PhyloP100
7.0
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.3
N
REVEL
Uncertain
0.33
Sift
Uncertain
0.011
D
Sift4G
Uncertain
0.054
T
Polyphen
0.89
P
Vest4
0.86
MVP
0.73
MPC
0.35
ClinPred
0.013
T
GERP RS
5.4
Varity_R
0.13
gMVP
0.29
Mutation Taster
=60/40
polymorphism

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

Other links and lift over

dbSNP: rs121908601; hg19: chr8-106431420; COSMIC: COSV68291556; API