16-87412146-T-A

Variant summary

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

The NM_015144.3(ZCCHC14):c.2575A>T(p.Thr859Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T859M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ZCCHC14
NM_015144.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.138

Variant links:

Genes affected

ZCCHC14 (HGNC:24134): (zinc finger CCHC-type containing 14) Predicted to enable nucleic acid binding activity; phosphatidylinositol binding activity; and zinc ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016482592).

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZCCHC14	NM_015144.3 linkuse as main transcript	c.2575A>T	p.Thr859Ser	missense_variant	12/13	ENST00000671377.2
ZCCHC14	XM_005255858.4 linkuse as main transcript	c.2575A>T	p.Thr859Ser	missense_variant	12/12
ZCCHC14	XM_017023082.3 linkuse as main transcript	c.2056A>T	p.Thr686Ser	missense_variant	12/12
ZCCHC14	XR_243401.4 linkuse as main transcript	n.3361A>T		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZCCHC14	ENST00000671377.2 linkuse as main transcript	c.2575A>T	p.Thr859Ser	missense_variant	12/13		NM_015144.3	P1
ZCCHC14	ENST00000268616.9 linkuse as main transcript	c.2164A>T	p.Thr722Ser	missense_variant	12/13	1			Q8WYQ9-1
ZCCHC14	ENST00000568020.6 linkuse as main transcript	c.2197A>T	p.Thr733Ser	missense_variant, NMD_transcript_variant	12/14	1
ZCCHC14	ENST00000561928.1 linkuse as main transcript	c.1816A>T	p.Thr606Ser	missense_variant	10/10	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250616

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000247

AC:

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 09, 2021

The c.2164A>T (p.T722S) alteration is located in exon 12 (coding exon 12) of the ZCCHC14 gene. This alteration results from a A to T substitution at nucleotide position 2164, causing the threonine (T) at amino acid position 722 to be replaced by a serine (S). 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

0.063

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.71

Cadd

Benign

2.7

Dann

Benign

0.27

DEOGEN2

Benign

0.028

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.42

M_CAP

Benign

0.0036

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.0

REVEL

Benign

0.074

Sift

Benign

0.16

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.094

MVP

0.043

MPC

0.24

ClinPred

0.021

GERP RS

-4.9

Varity_R

0.022

gMVP

0.23

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

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