X-65502120-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001010888.4(ZC3H12B):c.1422C>G(p.Ile474Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,096,392 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: ZC3H12B NM_001010888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

ZC3H12B (HGNC:17407): (zinc finger CCCH-type containing 12B) The protein encoded by this gene belongs to a family of CCCH-type zinc finger proteins that are involved in the proinflammatory activation of macrophages. The exact function of this family member is unknown, but it is thought to function as a ribonuclease. [provided by RefSeq, May 2010]

LAS1L (HGNC:25726): (LAS1 like ribosome biogenesis factor) Enables RNA binding activity. Predicted to be involved in maturation of 5.8S rRNA and maturation of LSU-rRNA. Located in membrane. Part of MLL1 complex. Implicated in Wilson-Turner syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038056165).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12B	NM_001010888.4	c.1422C>G	p.Ile474Met	missense_variant	10/10	ENST00000338957.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12B	ENST00000338957.5	c.1422C>G	p.Ile474Met	missense_variant	10/10	1	NM_001010888.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000168 AC: 3 AN: 178795 Hom.: 0 AF XY: 0.0000308 AC XY: 2 AN XY: 64971

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096392 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 2 AN XY: 361960

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: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

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

Jan 04, 2024

The c.1422C>G (p.I474M) alteration is located in exon 5 (coding exon 5) of the ZC3H12B gene. This alteration results from a C to G substitution at nucleotide position 1422, causing the isoleucine (I) at amino acid position 474 to be replaced by a methionine (M). 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	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	10
Dann	Benign	0.58
DEOGEN2	Benign	0.0011	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	0.68	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.052
Sift	Benign	0.30	T
Sift4G	Benign	0.23	T
Vest4		0.023
MVP		0.17
MPC		0.52
ClinPred		0.056	T
GERP RS		2.7
Varity_R		0.21
gMVP		0.10

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: rs747257073; hg19: chrX-64722000;