rs117908591

chr8-105802369-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012082.4(ZFPM2):c.2287G>A(p.Val763Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,613,702 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (17 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004432678).
• BP6: Variant 8-105802369-G-A is Benign according to our data. Variant chr8-105802369-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 414003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-105802369-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00322 (490/152238) while in subpopulation NFE AF= 0.00497 (338/68020). AF 95% confidence interval is 0.00453. There are 1 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 490 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFPM2	NM_012082.4	c.2287G>A	p.Val763Ile	missense_variant	8/8	ENST00000407775.7
ZFPM2-AS1	NR_125797.1	n.191-3927C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFPM2	ENST00000407775.7	c.2287G>A	p.Val763Ile	missense_variant	8/8	1	NM_012082.4	P1
ZFPM2-AS1	ENST00000520433.5	n.212-3927C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152120 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00266 AC: 656 AN: 247080 Hom.: 3 AF XY: 0.00271 AC XY: 364 AN XY: 134132

Gnomad AFR exome AF: 0.000653

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00426 AC: 6230 AN: 1461464 Hom.: 17 Cov.: 31 AF XY: 0.00420 AC XY: 3052 AN XY: 727012

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00322 AC: 490 AN: 152238 Hom.: 1 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74438

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00427 Hom.: 3

Bravo AF: 0.00305

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000750 AC: 3

ESP6500EA AF: 0.00444 AC: 37

ExAC AF: 0.00243 AC: 294

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ZFPM2: BP4, BS2 -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 08, 2017	- -

46,XY sex reversal 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.58	P;.;.
Vest4		0.10
MVP		0.14
MPC		0.12
ClinPred		0.010	T
GERP RS		4.7
Varity_R		0.031
gMVP		0.16

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: rs117908591; hg19: chr8-106814597; COSMIC: COSV105321146;