1-37475761-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025079.3(ZC3H12A):c.265G>A(p.Gly89Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZC3H12A NM_025079.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

Genes affected

ZC3H12A (HGNC:26259): (zinc finger CCCH-type containing 12A) ZC3H12A is an MCP1 (CCL2; MIM 158105)-induced protein that acts as a transcriptional activator and causes cell death of cardiomyocytes, possibly via induction of genes associated with apoptosis.[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31626284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12A	NM_025079.3	c.265G>A	p.Gly89Arg	missense_variant	2/6	ENST00000373087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12A	ENST00000373087.7	c.265G>A	p.Gly89Arg	missense_variant	2/6	1	NM_025079.3	P1
ZC3H12A	ENST00000640233.1	c.265G>A	p.Gly89Arg	missense_variant, NMD_transcript_variant	2/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250468 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135558

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.265G>A (p.G89R) alteration is located in exon 2 (coding exon 1) of the ZC3H12A gene. This alteration results from a G to A substitution at nucleotide position 265, causing the glycine (G) at amino acid position 89 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.36
Sift	Benign	0.056	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.23
MutPred		0.55		Gain of helix (P = 0.062);
MVP		0.043
MPC		0.66
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.45
gMVP		0.66

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: rs779999567; hg19: chr1-37941362;