rs35843564

chr8-105801358-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.1276G>A(p.Ala426Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,613,880 control chromosomes in the GnomAD database, including 3 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 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.290

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=0.0024237037).
• BP6: Variant 8-105801358-G-A is Benign according to our data. Variant chr8-105801358-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 544225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00276 (420/152206) while in subpopulation AFR AF= 0.0093 (386/41522). AF 95% confidence interval is 0.00853. There are 1 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 422 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFPM2	NM_012082.4	c.1276G>A	p.Ala426Thr	missense_variant	8/8	ENST00000407775.7
ZFPM2-AS1	NR_125797.1	n.191-2916C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFPM2	ENST00000407775.7	c.1276G>A	p.Ala426Thr	missense_variant	8/8	1	NM_012082.4	P1
ZFPM2-AS1	ENST00000520433.5	n.212-2916C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00935

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00110 AC: 273 AN: 248830 Hom.: 0 AF XY: 0.000933 AC XY: 126 AN XY: 135020

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00151

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000478 AC: 699 AN: 1461674 Hom.: 2 Cov.: 31 AF XY: 0.000485 AC XY: 353 AN XY: 727118

Gnomad4 AFR exome AF: 0.00959

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00154

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74414

Gnomad4 AFR AF: 0.00930

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000453 Hom.: 1

Bravo AF: 0.00312

ESP6500AA AF: 0.00867 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 174

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 17, 2019

- -

46,XY sex reversal 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

ZFPM2: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	14
Dann	Benign	0.82
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.70	T;.;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.043
MVP		0.12
MPC		0.094
ClinPred		0.0027	T
GERP RS		1.1
Varity_R		0.035
gMVP		0.20

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: rs35843564; hg19: chr8-106813586;