rs187043152

chr8-105801714-G-Achr8-105801714-G-T

Variant summary

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

The NM_012082.4(ZFPM2):c.1632G>A(p.Met544Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,784 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (17 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:7
• Conservation: PhyloP100: 8.00

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011999905).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00344 (524/152200) while in subpopulation NFE AF= 0.00516 (351/67996). AF 95% confidence interval is 0.00472. There are 1 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFPM2	NM_012082.4	c.1632G>A	p.Met544Ile	missense_variant	8/8	ENST00000407775.7
ZFPM2-AS1	NR_125797.1	n.191-3272C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFPM2	ENST00000407775.7	c.1632G>A	p.Met544Ile	missense_variant	8/8	1	NM_012082.4	P1
ZFPM2-AS1	ENST00000520433.5	n.212-3272C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 524 AN: 152082 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00338 AC: 837 AN: 247958 Hom.: 3 AF XY: 0.00329 AC XY: 443 AN XY: 134660

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.00487

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00460 AC: 6722 AN: 1461584 Hom.: 17 Cov.: 31 AF XY: 0.00437 AC XY: 3174 AN XY: 727080

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152200 Hom.: 1 Cov.: 32 AF XY: 0.00331 AC XY: 246 AN XY: 74426

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00415 Hom.: 1

Bravo AF: 0.00305

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00498 AC: 41

ExAC AF: 0.00343 AC: 414

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

46,XY sex reversal 9 Pathogenic:1 Benign:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in a sporadic case with TOF (De Luca 2011), one homozygous case with 46,XY gonadal dysgenesis (Bashamboo 2014), one case with congenital diaphragmatic hernia and was inherited from the mother (Longoni 2015). ExAC freq 0.5%. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2021	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ZFPM2: BS1, BS2 -

Tetralogy of Fallot Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2014

- -

ZFPM2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 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). -

46,XY sex reversal 3 Benign:1

Benign, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Aug 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.90	N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.14	B;.;.
Vest4		0.64
MutPred		0.32		Loss of solvent accessibility (P = 0.0352);.;.;
MVP		0.45
MPC		0.14
ClinPred		0.022	T
GERP RS		6.0
Varity_R		0.37
gMVP		0.37

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: rs187043152; hg19: chr8-106813942;