Genetic Variant ZFPM2:p.Met148Leu (chr8-105634267-A-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_012082.4(ZFPM2):c.442A>T(p.Met148Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M148V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Consequence

ZFPM2
NM_012082.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.44

Publications

1 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 links:

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

ZFPM2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.078594774).

BS2

High AC in GnomAd4 at 5 AD,Unknown gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012082.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFPM2	NM_012082.4	MANE Select	c.442A>T	p.Met148Leu	missense	Exon 5 of 8	NP_036214.2	Q8WW38-1
ZFPM2	NM_001362836.2		c.283A>T	p.Met95Leu	missense	Exon 4 of 7	NP_001349765.1
ZFPM2	NM_001362837.2		c.46A>T	p.Met16Leu	missense	Exon 5 of 8	NP_001349766.1	E7ET52

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFPM2	ENST00000407775.7	TSL:1 MANE Select	c.442A>T	p.Met148Leu	missense	Exon 5 of 8	ENSP00000384179.2	Q8WW38-1
ZFPM2	ENST00000511341.6	TSL:1	n.1182A>T		non_coding_transcript_exon	Exon 5 of 6
ZFPM2	ENST00000941376.1		c.439A>T	p.Met147Leu	missense	Exon 5 of 8	ENSP00000611435.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.15

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.81

M_CAP

Benign

0.0060

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.81

PhyloP100

4.4

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.16

REVEL

Benign

0.087

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.37

MutPred

0.36

Gain of catalytic residue at M148 (P = 0.0577)

MVP

0.33

MPC

0.090

ClinPred

0.21

GERP RS

5.6

Varity_R

0.071

gMVP

0.27

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over