rs1811743429

Variant names:

• chr8-105419176-G-A
• rs1811743429
• NM_012082.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012082.4(ZFPM2):​c.73G>A​(p.Glu25Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E25G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.42
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.73G>A	p.Glu25Lys	missense	Exon 2 of 8	NP_036214.2	Q8WW38-1
	ZFPM2	NM_001362837.2		c.-324G>A		5_prime_UTR	Exon 2 of 8	NP_001349766.1	E7ET52
	ZFPM2	NM_001362836.2		c.41-25104G>A		intron	N/A	NP_001349765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFPM2	ENST00000407775.7	TSL:1 MANE Select	c.73G>A	p.Glu25Lys	missense	Exon 2 of 8	ENSP00000384179.2	Q8WW38-1
	ZFPM2	ENST00000511341.6	TSL:1	n.813G>A		non_coding_transcript_exon	Exon 2 of 6
	ZFPM2	ENST00000941376.1		c.73G>A	p.Glu25Lys	missense	Exon 2 of 8	ENSP00000611435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.033	D
Sift4G	Uncertain	0.023	D
Polyphen		0.25	B
Vest4		0.68
MutPred		0.22		Gain of methylation at E25 (P = 0.004)
MVP		0.58
MPC		0.53
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.26
gMVP		0.37
Mutation Taster		=71/29	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: rs1811743429; hg19: chr8-106431404;