16-88577585-T-G

Position:

• chr16-88577585-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144604.4(ZC3H18):​c.462T>G​(p.Asp154Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZC3H18 NM_144604.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.83

Genes affected

ZC3H18 (HGNC:25091): (zinc finger CCCH-type containing 18) Enables mRNA cap binding complex binding activity and protein-macromolecule adaptor activity. Involved in RNA destabilization. Located in nuclear speck. Part of ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018094212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H18	NM_144604.4	c.462T>G	p.Asp154Glu	missense_variant	2/18	ENST00000301011.10	NP_653205.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3H18	ENST00000301011.10	c.462T>G	p.Asp154Glu	missense_variant	2/18	1	NM_144604.4	ENSP00000301011.5
ZC3H18	ENST00000452588.6	c.462T>G	p.Asp154Glu	missense_variant	2/19	2		ENSP00000416951.2
ZC3H18	ENST00000569435.5	c.252+210T>G		intron_variant		5		ENSP00000455260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Mar 23, 2023

The c.462T>G (p.D154E) alteration is located in exon 2 (coding exon 1) of the ZC3H18 gene. This alteration results from a T to G substitution at nucleotide position 462, causing the aspartic acid (D) at amino acid position 154 to be replaced by a glutamic acid (E). 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	0.070
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0010
DANN	Benign	0.47
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.051
Sift	Benign	0.33	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.077
MutPred		0.054		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.043
MPC		0.018
ClinPred		0.11	T
GERP RS		-11
Varity_R		0.025
gMVP		0.0032

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-88643993;