chr6-109481892-A-C

Variant names:

• chr6-109481892-A-C
• NM_014797.3:c.135T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014797.3(ZBTB24):​c.135T>G​(p.Asn45Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZBTB24 NM_014797.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610

Genes affected

ZBTB24 (HGNC:21143): (zinc finger and BTB domain containing 24) Predicted to enable DNA-binding transcription factor activity 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 act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be located in nucleus. Implicated in immunodeficiency-centromeric instability-facial anomalies syndrome 2. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB24	NM_014797.3	c.135T>G	p.Asn45Lys	missense_variant	Exon 2 of 7	ENST00000230122.4	NP_055612.2
ZBTB24	NM_001164313.2	c.135T>G	p.Asn45Lys	missense_variant	Exon 2 of 2		NP_001157785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB24	ENST00000230122.4	c.135T>G	p.Asn45Lys	missense_variant	Exon 2 of 7	1	NM_014797.3	ENSP00000230122.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 2 Uncertain:1

Apr 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with ZBTB24-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 45 of the ZBTB24 protein (p.Asn45Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.081	T
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.76		Gain of methylation at N45 (P = 0.0157);
MVP		0.45
MPC		0.63
ClinPred		0.90	D
GERP RS		-1.1
Varity_R		0.10
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-109803095;