14-104801597-G-A

Variant summary

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

The NM_001137601.3(ZBTB42):c.400G>A(p.Ala134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,549,842 control chromosomes in the GnomAD database, including 9,323 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (766 hom., cov: 34)
  • Exomes 𝑓: 0.11 (8557 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.356

Genes affected

ZBTB42 (HGNC:32550): (zinc finger and BTB domain containing 42) The protein encoded by this gene is a member of the C2H2 zinc finger protein family. This protein is predicted to have a pox virus and zinc finger (POZ) domain at the N-terminus and four zinc finger domains at the C-terminus. In human and mouse, the protein localizes to the nuclei of skeletal muscle cells. Knockdown of this gene in zebrafish results in abnormal skeletal muscle development and myofibrillar disorganization. A novel homozygous variant of the human gene has been associated with lethal congenital contracture syndrome, an autosomal recessive disorder that results in muscle wasting. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015160143).
• BP6: Variant 14-104801597-G-A is Benign according to our data. Variant chr14-104801597-G-A is described in ClinVar as [Benign]. Clinvar id is 1266544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB42	NM_001137601.3	c.400G>A	p.Ala134Thr	missense_variant	1/1	ENST00000342537.8
ZBTB42	NM_001370342.1	c.400G>A	p.Ala134Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB42	ENST00000342537.8	c.400G>A	p.Ala134Thr	missense_variant	1/1		NM_001137601.3	P1
ZBTB42	ENST00000555360.1	c.400G>A	p.Ala134Thr	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12863 AN: 152110 Hom.: 766 Cov.: 34

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0784

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.0925 AC: 13771 AN: 148924 Hom.: 787 AF XY: 0.0940 AC XY: 7461 AN XY: 79414

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0615

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0679

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.106 AC: 147994 AN: 1397614 Hom.: 8557 Cov.: 89 AF XY: 0.106 AC XY: 73118 AN XY: 689254

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.0655

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.0978

GnomAD4 genome AF: 0.0845 AC: 12863 AN: 152228 Hom.: 766 Cov.: 34 AF XY: 0.0848 AC XY: 6314 AN XY: 74432

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.0783

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.0875

Alfa AF: 0.110 Hom.: 1041

Bravo AF: 0.0776

TwinsUK AF: 0.123 AC: 455

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0210 AC: 29

ESP6500EA AF: 0.118 AC: 376

ExAC AF: 0.0716 AC: 1903

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

ZBTB42-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 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	0.097
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.9
Dann	Benign	0.72
DEOGEN2	Benign	0.0027	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.076	N
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.023
Sift	Benign	0.61	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0030	B;B
Vest4		0.021
ClinPred		0.0014	T
GERP RS		-2.4
Varity_R		0.026

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: rs34284721; hg19: chr14-105267934; COSMIC: COSV61136894;