13-45965312-C-A

Position:

• chr13-45965312-C-A

Variant summary

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

The NM_001330564.2(ZC3H13):​c.4442G>T​(p.Arg1481Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZC3H13 NM_001330564.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

Genes affected

ZC3H13 (HGNC:20368): (zinc finger CCCH-type containing 13) Enables RNA binding activity. Involved in mRNA methylation. Located in nuclear speck. Part of RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.32068422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H13	NM_001330564.2	c.4442G>T	p.Arg1481Met	missense_variant	16/19	ENST00000679008.1	NP_001317493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3H13	ENST00000679008.1	c.4442G>T	p.Arg1481Met	missense_variant	16/19		NM_001330564.2	ENSP00000503994	A2
ZC3H13	ENST00000282007.7	c.4442G>T	p.Arg1481Met	missense_variant	16/17	1		ENSP00000282007	P2
ZC3H13	ENST00000242848.8	c.4439G>T	p.Arg1480Met	missense_variant	16/19	5		ENSP00000242848	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 14, 2022

The c.4442G>T (p.R1481M) alteration is located in exon 16 (coding exon 15) of the ZC3H13 gene. This alteration results from a G to T substitution at nucleotide position 4442, causing the arginine (R) at amino acid position 1481 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.26		Gain of helix (P = 0.062);.;
MVP		0.082
MPC		0.38
ClinPred		0.78	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.28

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: rs752685699; hg19: chr13-46539447; COSMIC: COSV99667940;