8-105318993-C-G

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.40+12C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,491,686 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (2 hom., cov: 32)
  • Exomes 𝑓: 0.011 (112 hom.)
• Consequence: ZFPM2 NM_012082.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-105318993-C-G is Benign according to our data. Variant chr8-105318993-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1558608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00694 (1057/152196) while in subpopulation NFE AF= 0.0116 (790/67998). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFPM2	NM_012082.4	c.40+12C>G		intron_variant		ENST00000407775.7
ZFPM2	NM_001362836.2	c.40+12C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFPM2	ENST00000407775.7	c.40+12C>G		intron_variant		1	NM_012082.4	P1
ZFPM2	ENST00000518180.1	n.479+72464C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152078 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00898

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00610 AC: 727 AN: 119206 Hom.: 7 AF XY: 0.00624 AC XY: 403 AN XY: 64612

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00365

Gnomad FIN exome AF: 0.00779

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.0113 AC: 15070 AN: 1339490 Hom.: 112 Cov.: 31 AF XY: 0.0110 AC XY: 7281 AN XY: 660926

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.0000653

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.00906

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00986

GnomAD4 genome AF: 0.00694 AC: 1057 AN: 152196 Hom.: 2 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74402

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00898

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00334 Hom.: 2

Bravo AF: 0.00643

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

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

Jan 16, 2024

- -

Tetralogy of Fallot;C1857781:Diaphragmatic hernia 3;C4015129:46,XY sex reversal 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Benign	0.87

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: rs149902904; hg19: chr8-106331221;