1-37475795-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025079.3(ZC3H12A):c.299C>T(p.Pro100Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,612,496 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: ZC3H12A NM_025079.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0670

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003866762).
• BP6: Variant 1-37475795-C-T is Benign according to our data. Variant chr1-37475795-C-T is described in ClinVar as [Benign]. Clinvar id is 784945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00531 (808/152302) while in subpopulation AFR AF= 0.0183 (760/41566). AF 95% confidence interval is 0.0172. There are 9 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12A	NM_025079.3	c.299C>T	p.Pro100Leu	missense_variant	2/6	ENST00000373087.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12A	ENST00000373087.7	c.299C>T	p.Pro100Leu	missense_variant	2/6	1	NM_025079.3	P1
ZC3H12A	ENST00000640233.1	c.299C>T	p.Pro100Leu	missense_variant, NMD_transcript_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 806 AN: 152184 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

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: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00179 AC: 445 AN: 248784 Hom.: 1 AF XY: 0.00130 AC XY: 176 AN XY: 134872

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.00447

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000641 AC: 936 AN: 1460194 Hom.: 12 Cov.: 31 AF XY: 0.000536 AC XY: 389 AN XY: 726194

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.00403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00531 AC: 808 AN: 152302 Hom.: 9 Cov.: 33 AF XY: 0.00513 AC XY: 382 AN XY: 74476

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000988 Hom.: 1

Bravo AF: 0.00651

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	18
Dann	Benign	0.64
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.083
Sift	Benign	0.45	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.049
MVP		0.043
MPC		0.54
ClinPred		0.0021	T
GERP RS		2.2
Varity_R		0.023
gMVP		0.21

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: rs34702192; hg19: chr1-37941396; COSMIC: COSV66104324; COSMIC: COSV66104324;