1-37483595-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025079.3(ZC3H12A):c.1784A>G(p.Gln595Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,455,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ZC3H12A NM_025079.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08855334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12A	NM_025079.3	c.1784A>G	p.Gln595Arg	missense_variant	6/6	ENST00000373087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12A	ENST00000373087.7	c.1784A>G	p.Gln595Arg	missense_variant	6/6	1	NM_025079.3	P1
ZC3H12A	ENST00000640233.1	c.*1016A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1455958 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 724152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Oct 19, 2021

The c.1784A>G (p.Q595R) alteration is located in exon 6 (coding exon 5) of the ZC3H12A gene. This alteration results from a A to G substitution at nucleotide position 1784, causing the glutamine (Q) at amino acid position 595 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	Benign	0.069
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.54	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.042
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.062
MutPred		0.31		Gain of phosphorylation at S594 (P = 0.0892);
MVP		0.16
MPC		0.57
ClinPred		0.39	T
GERP RS		3.8
Varity_R		0.071
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs770081007; hg19: chr1-37949196;