rs146423225

Positions:

• chr8-105802747-C-G
• chr8-105802747-C-T

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.2665C>G​(p.Gln889Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,613,490 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (112 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.25

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=0.001937449).
• BP6: Variant 8-105802747-C-G is Benign according to our data. Variant chr8-105802747-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 240843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFPM2	NM_012082.4	c.2665C>G	p.Gln889Glu	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.2665C>G	p.Gln889Glu	missense_variant	8/8	1	NM_012082.4	ENSP00000384179.2

Frequencies

GnomAD3 genomes AF: 0.00522 AC: 795 AN: 152154 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.0105 AC: 2605 AN: 247732 Hom.: 86 AF XY: 0.00812 AC XY: 1092 AN XY: 134420

Gnomad AFR exome AF: 0.000654

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.000335

Gnomad SAS exome AF: 0.000656

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.00666

GnomAD4 exome AF: 0.00285 AC: 4158 AN: 1461218 Hom.: 112 Cov.: 32 AF XY: 0.00255 AC XY: 1852 AN XY: 726854

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0518

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000859

Gnomad4 FIN exome AF: 0.0231

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152272 Hom.: 18 Cov.: 32 AF XY: 0.00637 AC XY: 474 AN XY: 74448

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.0267

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0231

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00100 Hom.: 2

Bravo AF: 0.00650

ESP6500AA AF: 0.000514 AC: 2

ESP6500EA AF: 0.000724 AC: 6

ExAC AF: 0.00812 AC: 982

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2018	- -

46,XY sex reversal 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

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	0.078
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.95	D;.;D
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.035	D;D;D
Sift4G	Uncertain	0.046	D;D;D
Polyphen		0.0020	B;.;.
Vest4		0.22
MPC		0.11
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.087
gMVP		0.27

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: rs146423225; hg19: chr8-106814975;