8-105419233-G-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012082.4(ZFPM2):​c.130G>A​(p.Glu44Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,678 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ZFPM2
NM_012082.4 missense

Scores

1
4
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.50

Publications

0 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 -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03306207).
BP6
Variant 8-105419233-G-A is Benign according to our data. Variant chr8-105419233-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 633465.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000591 (9/152266) while in subpopulation SAS AF = 0.00187 (9/4824). AF 95% confidence interval is 0.000973. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 9 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZFPM2NM_012082.4 linkc.130G>A p.Glu44Lys 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.130G>A p.Glu44Lys missense_variant Exon 2 of 8 1 NM_012082.4 ENSP00000384179.2 Q8WW38-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152148
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000261
AC:
65
AN:
248920
AF XY:
0.000355
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000110
AC:
161
AN:
1461412
Hom.:
1
Cov.:
31
AF XY:
0.000155
AC XY:
113
AN XY:
726978
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44710
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39664
South Asian (SAS)
AF:
0.00183
AC:
158
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111706
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60358
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
9
18
28
37
46
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.0000591
AC:
9
AN:
152266
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41554
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00187
AC:
9
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.000315
AC:
38
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Diaphragmatic hernia 3 Uncertain:1
Jan 01, 2019
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

46,XY sex reversal 9 Benign:1
May 23, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ZFPM2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.033
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L
PhyloP100
9.5
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.17
Sift
Benign
0.044
D
Sift4G
Benign
0.34
T
Polyphen
0.083
B
Vest4
0.80
MutPred
0.38
Gain of ubiquitination at E44 (P = 0.0016);
MVP
0.61
MPC
0.15
ClinPred
0.21
T
GERP RS
5.4
Varity_R
0.23
gMVP
0.30
Mutation Taster
=255/45
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: rs569356297; hg19: chr8-106431461; COSMIC: COSV105348064; API