13-45965414-T-C

Position:

• chr13-45965414-T-C

Variant summary

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

The NM_001330564.2(ZC3H13):​c.4340A>G​(p.Lys1447Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,978 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: 0.0000014 (0 hom.)
• Consequence: ZC3H13 NM_001330564.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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=0.29784447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H13	NM_001330564.2	c.4340A>G	p.Lys1447Arg	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.4340A>G	p.Lys1447Arg	missense_variant	16/19		NM_001330564.2	ENSP00000503994	A2
ZC3H13	ENST00000282007.7	c.4340A>G	p.Lys1447Arg	missense_variant	16/17	1		ENSP00000282007	P2
ZC3H13	ENST00000242848.8	c.4337A>G	p.Lys1446Arg	missense_variant	16/19	5		ENSP00000242848	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460978 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726842

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000470 Hom.: 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

Dec 19, 2022

The c.4340A>G (p.K1447R) alteration is located in exon 16 (coding exon 15) of the ZC3H13 gene. This alteration results from a A to G substitution at nucleotide position 4340, causing the lysine (K) at amino acid position 1447 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	0.12
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;D
Vest4		0.30
MutPred		0.14		Loss of ubiquitination at K1446 (P = 3e-04);.;
MVP		0.16
MPC		0.28
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.098

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1451805842; hg19: chr13-46539549;