chr16-88577228-T-G

Position:

• chr16-88577228-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_144604.4(ZC3H18):​c.105T>G​(p.Asp35Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZC3H18 NM_144604.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.902

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019937724).
• BP6: Variant 16-88577228-T-G is Benign according to our data. Variant chr16-88577228-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2512327.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H18	NM_144604.4	c.105T>G	p.Asp35Glu	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.105T>G	p.Asp35Glu	missense_variant	2/18	1	NM_144604.4	ENSP00000301011.5
ZC3H18	ENST00000452588.6	c.105T>G	p.Asp35Glu	missense_variant	2/19	2		ENSP00000416951.2
ZC3H18	ENST00000569435.5	c.105T>G	p.Asp35Glu	missense_variant	2/6	5		ENSP00000455260.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.3
DANN	Benign	0.86
DEOGEN2	Benign	0.025	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.94	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.064
MutPred		0.13		Gain of solvent accessibility (P = 0.1751);Gain of solvent accessibility (P = 0.1751);Gain of solvent accessibility (P = 0.1751);
MVP		0.043
MPC		0.018
ClinPred		0.040	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.019
gMVP		0.012

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: rs1914810157; hg19: chr16-88643636;