Variant X-104114974-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001143978.3(ZCCHC18):c.863C>T(p.Ser288Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,080,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000031 ( 0 hom. 13 hem. )

Consequence

ZCCHC18
NM_001143978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.750

Variant links:

Genes affected

ZCCHC18 (HGNC:32459): (zinc finger CCHC-type containing 18) Predicted to enable metal ion binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC18 links:

SLC25A53 (HGNC:31894): (solute carrier family 25 member 53) Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC25A53 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02676475).

BS2

High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZCCHC18	NM_001143978.3 linkuse as main transcript	c.863C>T	p.Ser288Leu	missense_variant	3/3	ENST00000650639.1	NP_001137450.1
SLC25A53	NM_001012755.5 linkuse as main transcript	c.-31-9686G>A		intron_variant		ENST00000594199.3	NP_001012773.2
ZCCHC18	XM_011531012.4 linkuse as main transcript	c.863C>T	p.Ser288Leu	missense_variant	3/3		XP_011529314.1
ZCCHC18	NR_026694.3 linkuse as main transcript	n.672-278C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZCCHC18	ENST00000650639.1 linkuse as main transcript	c.863C>T	p.Ser288Leu	missense_variant	3/3		NM_001143978.3	ENSP00000498828	P1
SLC25A53	ENST00000594199.3 linkuse as main transcript	c.-31-9686G>A		intron_variant		1	NM_001012755.5	ENSP00000468980	P1
ZCCHC18	ENST00000537356.3 linkuse as main transcript	c.863C>T	p.Ser288Leu	missense_variant	2/2	5		ENSP00000473824	P1
ZCCHC18	ENST00000422784.5 linkuse as main transcript	n.651-278C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000269

AC:

AN:

148694

Hom.:

AF XY:

0.0000436

AC XY:

AN XY:

45854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000837

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000159

Gnomad OTH exome

AF:

0.000256

GnomAD4 exome

AF:

0.0000305

AC:

AN:

1080524

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

351604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000923

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:

0.0000336

Gnomad4 OTH exome

AF:

0.0000440

GnomAD4 genome

Cov.:

Alfa

AF:

0.000223

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2021

The c.863C>T (p.S288L) alteration is located in exon 3 (coding exon 1) of the ZCCHC18 gene. This alteration results from a C to T substitution at nucleotide position 863, causing the serine (S) at amino acid position 288 to be replaced by a leucine (L). 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

0.077

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.9

DANN

Benign

0.50

DEOGEN2

Benign

0.0076

T;T

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.33

.;T

M_CAP

Benign

0.00059

MetaRNN

Benign

0.027

T;T

MutationAssessor

Benign

-0.55

N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.38

Sift4G

Benign

0.35

T;T

Polyphen

0.0

B;B

Vest4

0.047

MVP

0.055

MPC

0.15

GERP RS

-1.2

Varity_R

0.044

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over