rs767896734

Variant names:

• chr8-105419237-G-A
• rs767896734
• NM_012082.4:c.134G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-105419237-G-A
• chr8-105419237-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012082.4(ZFPM2):​c.134G>A​(p.Ser45Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. S45I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZFPM2 NM_012082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 1 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: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08280295).

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.134G>A	p.Ser45Asn	missense	Exon 2 of 8	NP_036214.2	Q8WW38-1
	ZFPM2	NM_001362837.2		c.-263G>A		5_prime_UTR	Exon 2 of 8	NP_001349766.1	E7ET52
	ZFPM2	NM_001362836.2		c.41-25043G>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.134G>A	p.Ser45Asn	missense	Exon 2 of 8	ENSP00000384179.2	Q8WW38-1
	ZFPM2	ENST00000511341.6	TSL:1	n.874G>A		non_coding_transcript_exon	Exon 2 of 6
	ZFPM2	ENST00000941376.1		c.134G>A	p.Ser45Asn	missense	Exon 2 of 8	ENSP00000611435.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726986

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111712

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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	0.056
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N
PhyloP100		4.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.098
Sift	Benign	0.57	T
Sift4G	Benign	0.56	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.15		Loss of phosphorylation at S45 (P = 0.015)
MVP		0.29
MPC		0.090
ClinPred		0.71	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.060
Mutation Taster		=282/18	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: rs767896734; hg19: chr8-106431465; COSMIC: COSV101343564;