rs202217256

chr8-105444372-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_012082.4(ZFPM2):c.292G>A(p.Asp98Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,610,248 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.24

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012410402).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00299 (456/152332) while in subpopulation NFE AF= 0.00536 (365/68036). AF 95% confidence interval is 0.00491. There are 4 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFPM2	NM_012082.4	c.292G>A	p.Asp98Asn	missense_variant	3/8	ENST00000407775.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFPM2	ENST00000407775.7	c.292G>A	p.Asp98Asn	missense_variant	3/8	1	NM_012082.4	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00256 AC: 627 AN: 244512 Hom.: 4 AF XY: 0.00260 AC XY: 344 AN XY: 132404

Gnomad AFR exome AF: 0.000994

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.00145

Gnomad FIN exome AF: 0.000935

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00453 AC: 6598 AN: 1457916 Hom.: 17 Cov.: 29 AF XY: 0.00442 AC XY: 3204 AN XY: 724904

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.000585

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00550

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.00299 AC: 456 AN: 152332 Hom.: 4 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74490

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00536

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00432 Hom.: 6

Bravo AF: 0.00267

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00159 AC: 6

ESP6500EA AF: 0.00474 AC: 39

ExAC AF: 0.00277 AC: 334

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,XY sex reversal 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ZFPM2: BS1, BS2 -

46,XY sex reversal 3 Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

ZFPM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2019

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	0.22
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.091
Sift	Benign	0.42	T
Sift4G	Benign	0.85	T
Polyphen		0.91	P
Vest4		0.73
MVP		0.77
MPC		0.50
ClinPred		0.021	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.38

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: rs202217256; hg19: chr8-106456600; COSMIC: COSV105348122;