Variant 19-57590287-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010879.4(ZIK1):c.476T>C(p.Leu159Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ZIK1
NM_001010879.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.864

Variant links:

Genes affected

ZIK1 (HGNC:33104): (zinc finger protein interacting with K protein 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZIK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.00892511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZIK1	NM_001010879.4 linkuse as main transcript	c.476T>C	p.Leu159Pro	missense_variant	4/4	ENST00000597850.2	NP_001010879.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZIK1	ENST00000597850.2 linkuse as main transcript	c.476T>C	p.Leu159Pro	missense_variant	4/4	1	NM_001010879.4	ENSP00000472867	P2	Q3SY52-1
ZIK1	ENST00000599456.1 linkuse as main transcript	c.311T>C	p.Leu104Pro	missense_variant	3/3	1		ENSP00000468937		Q3SY52-2
ZIK1	ENST00000307468.4 linkuse as main transcript	c.*220T>C		3_prime_UTR_variant	2/2	1		ENSP00000303820
ZIK1	ENST00000536878.6 linkuse as main transcript	c.437T>C	p.Leu146Pro	missense_variant	3/3	2		ENSP00000438487	A2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251240

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000137

AC:

201

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00486

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000197

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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

Jan 31, 2023

The c.476T>C (p.L159P) alteration is located in exon 4 (coding exon 4) of the ZIK1 gene. This alteration results from a T to C substitution at nucleotide position 476, causing the leucine (L) at amino acid position 159 to be replaced by a proline (P). 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

0.21

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.58

CADD

Benign

7.5

DANN

Benign

0.96

DEOGEN2

Benign

0.10

.;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.13

T;T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.0089

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Benign

0.12

Sift

Benign

0.28

T;.;.

Sift4G

Benign

0.27

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.28

MVP

0.19

MPC

0.76

ClinPred

0.10

GERP RS

-2.1

Varity_R

0.23

gMVP

0.088

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