chr8-105444372-G-A

Variant names:

• chr8-105444372-G-A
• rs202217256
• NM_012082.4:c.292G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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 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 criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.24
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• 46,XY sex reversal 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• diaphragmatic hernia 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• tetralogy of fallot

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012410402).
• BP6: Variant 8-105444372-G-A is Benign according to our data. Variant chr8-105444372-G-A is described in ClinVar as Benign. ClinVar VariationId is 240844.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 = 0.00299 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 456 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012082.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFPM2	NM_012082.4	MANE Select	c.292G>A	p.Asp98Asn	missense	Exon 3 of 8	NP_036214.2
	ZFPM2	NM_001362836.2		c.133G>A	p.Asp45Asn	missense	Exon 2 of 7	NP_001349765.1
	ZFPM2	NM_001362837.2		c.-105G>A		5_prime_UTR	Exon 3 of 8	NP_001349766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFPM2	ENST00000407775.7	TSL:1 MANE Select	c.292G>A	p.Asp98Asn	missense	Exon 3 of 8	ENSP00000384179.2
	ZFPM2	ENST00000511341.6	TSL:1	n.1032G>A		non_coding_transcript_exon	Exon 3 of 6
	ZFPM2	ENST00000941376.1		c.292G>A	p.Asp98Asn	missense	Exon 3 of 8	ENSP00000611435.1

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

GnomAD2 exomes AF: 0.00256 AC: 627 AN: 244512 AF XY: 0.00260

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 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

African (AFR) AF: 0.000658 AC: 22 AN: 33418

American (AMR) AF: 0.000585 AC: 26 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 45 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00160 AC: 137 AN: 85396

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53282

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00550 AC: 6106 AN: 1109694

Other (OTH) AF: 0.00335 AC: 202 AN: 60258

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

African (AFR) AF: 0.000914 AC: 38 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00536 AC: 365 AN: 68036

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00420 Hom.: 8

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	46,XY sex reversal 3 (1)
-	-	1	46,XY sex reversal 9 (1)
-	-	1	not provided (1)
-	-	1	ZFPM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.2
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
Mutation Taster		=268/32	polymorphism

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

Other links and lift over

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