1-22491503-G-A

Position:

chr1-22491503-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000375647.5(ZBTB40):c.801G>A(p.Met267Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,613,948 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.028 ( 206 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 170 hom. )

Consequence

ZBTB40
ENST00000375647.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.265

Variant links:

Genes affected

ZBTB40 (HGNC:29045): (zinc finger and BTB domain containing 40) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in cellular response to DNA damage stimulus. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB40 links:

ZBTB40 (HGNC:):

ZBTB40 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001978755).

BP6

Variant 1-22491503-G-A is Benign according to our data. Variant chr1-22491503-G-A is described in ClinVar as [Benign]. Clinvar id is 784937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.092 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB40	NM_014870.4 linkuse as main transcript	c.801G>A	p.Met267Ile	missense_variant	3/18	ENST00000375647.5	NP_055685.3	Q9NUA8-1Q1RMZ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB40	ENST00000375647.5 linkuse as main transcript	c.801G>A	p.Met267Ile	missense_variant	3/18	1	NM_014870.4	ENSP00000364798.4		Q9NUA8-1

Frequencies

GnomAD3 genomes

AF:

0.0275

AC:

4185

AN:

152118

Hom.:

207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.00728

AC:

1827

AN:

251034

Hom.:

AF XY:

0.00535

AC XY:

726

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.0937

Gnomad AMR exome

AF:

0.00683

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00294

AC:

4304

AN:

1461712

Hom.:

170

Cov.:

AF XY:

0.00259

AC XY:

1887

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0947

Gnomad4 AMR exome

AF:

0.00722

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000299

Gnomad4 OTH exome

AF:

0.00715

GnomAD4 genome

AF:

0.0275

AC:

4189

AN:

152236

Hom.:

206

Cov.:

AF XY:

0.0264

AC XY:

1962

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0944

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.00480

Hom.:

Bravo

AF:

0.0311

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0901

AC:

397

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00886

AC:

1075

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2018	- -

ZBTB40-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.014

.;T;T;T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.43

T;T;T;T;.

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.23

.;N;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.029

.;D;D;D;D

Sift4G

Uncertain

0.010

.;D;D;T;D

Polyphen

0.0

.;B;B;.;B

Vest4

0.19, 0.18, 0.16

MutPred

0.19

Loss of ubiquitination at K264 (P = 0.0533);Loss of ubiquitination at K264 (P = 0.0533);Loss of ubiquitination at K264 (P = 0.0533);Loss of ubiquitination at K264 (P = 0.0533);Loss of ubiquitination at K264 (P = 0.0533);

MVP

0.40

MPC

0.13

ClinPred

0.020

GERP RS

-2.9

Varity_R

0.063

gMVP

0.11

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