Genetic Variant NM_001369741.1:c.1522G>A (chr20-63747178-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001369741.1(ZBTB46):c.1522G>A(p.Gly508Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,608,882 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 0.000099 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ZBTB46
NM_001369741.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Variant links:

Genes affected

ZBTB46 (HGNC:16094): (zinc finger and BTB domain containing 46) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within regulation of leukocyte differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB46 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13836372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB46	NM_001369741.1 link	c.1522G>A	p.Gly508Ser	missense_variant	Exon 5 of 5	ENST00000245663.9	NP_001356670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBTB46	ENST00000245663.9 link	c.1522G>A	p.Gly508Ser	missense_variant	Exon 5 of 5	5	NM_001369741.1	ENSP00000245663.3	Q86UZ6
ZBTB46	ENST00000302995.2 link	c.1522G>A	p.Gly508Ser	missense_variant	Exon 5 of 7	2		ENSP00000303102.2	Q86UZ6
ZBTB46	ENST00000395104.5 link	c.1522G>A	p.Gly508Ser	missense_variant	Exon 4 of 4	2		ENSP00000378536.1	Q86UZ6

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000865

AC:

AN:

231204

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

127388

show subpopulations

Gnomad AFR exome

AF:

0.000285

Gnomad AMR exome

AF:

0.0000295

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1457064

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

724586

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151818

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74140

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1522G>A (p.G508S) alteration is located in exon 5 (coding exon 4) of the ZBTB46 gene. This alteration results from a G to A substitution at nucleotide position 1522, causing the glycine (G) at amino acid position 508 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

0.16

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.015

T;T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.76

.;.;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.42

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.54

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.18

MVP

0.25

MPC

0.089

ClinPred

0.12

GERP RS

4.2

Varity_R

0.074

gMVP

0.58

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