rs28374544

Positions:

• chr8-105802051-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012082.4(ZFPM2):​c.1969A>G​(p.Ser657Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00783 in 1,613,788 control chromosomes in the GnomAD database, including 824 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (425 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (399 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 4.99

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002689898).
• BP6: Variant 8-105802051-A-G is Benign according to our data. Variant chr8-105802051-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 6127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFPM2	NM_012082.4	c.1969A>G	p.Ser657Gly	missense_variant	8/8	ENST00000407775.7	NP_036214.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFPM2	ENST00000407775.7	c.1969A>G	p.Ser657Gly	missense_variant	8/8	1	NM_012082.4	ENSP00000384179.2

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6281 AN: 152134 Hom.: 426 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0106 AC: 2620 AN: 247912 Hom.: 151 AF XY: 0.00800 AC XY: 1077 AN XY: 134582

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00857

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.00481

GnomAD4 exome AF: 0.00434 AC: 6350 AN: 1461536 Hom.: 399 Cov.: 31 AF XY: 0.00376 AC XY: 2732 AN XY: 727036

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.00955

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0413 AC: 6290 AN: 152252 Hom.: 425 Cov.: 32 AF XY: 0.0386 AC XY: 2872 AN XY: 74438

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.00789 Hom.: 109

Bravo AF: 0.0470

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.131 AC: 486

ESP6500EA AF: 0.000731 AC: 6

ExAC AF: 0.0125 AC: 1515

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000712

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Tetralogy of Fallot Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 10, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.0
DANN	Benign	0.86
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.29	T;.;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.020	B;.;.
Vest4		0.041
MPC		0.096
ClinPred		0.020	T
GERP RS		4.4
Varity_R		0.041
gMVP		0.18

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

Other links and lift over

dbSNP: rs28374544; hg19: chr8-106814279; COSMIC: COSV65874397;