chr1-22491503-G-A

Position:

• chr1-22491503-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014870.4(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 NM_014870.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.265

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 (HGNC:):

ACMG classification

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	c.801G>A	p.Met267Ile	missense_variant	3/18	ENST00000375647.5	NP_055685.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4185 AN: 152118 Hom.: 207 Cov.: 32

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.: 76 AF XY: 0.00535 AC XY: 726 AN XY: 135730

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.: 32 AF XY: 0.00259 AC XY: 1887 AN XY: 727178

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.: 32 AF XY: 0.0264 AC XY: 1962 AN XY: 74436

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.: 49

Bravo AF: 0.0311

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0901 AC: 397

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00886 AC: 1075

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
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	N
LIST_S2	Benign	0.43	T;T;T;T;.
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.;.;N
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs36115661; hg19: chr1-22817996; COSMIC: COSV100988770;