1-6582079-G-A

Position:

• chr1-6582079-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000377674.9(ZBTB48):​c.712G>A​(p.Glu238Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZBTB48 ENST00000377674.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

Genes affected

ZBTB48 (HGNC:4930): (zinc finger and BTB domain containing 48) Enables double-stranded telomeric DNA binding activity; identical protein binding activity; and transcription cis-regulatory region binding activity. Involved in positive regulation of transcription, DNA-templated and telomere maintenance via telomere lengthening. Located in chromosome, telomeric region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.23067686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB48	NM_005341.4	c.712G>A	p.Glu238Lys	missense_variant	3/11	ENST00000377674.9	NP_005332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB48	ENST00000377674.9	c.712G>A	p.Glu238Lys	missense_variant	3/11	1	NM_005341.4	ENSP00000366902.4
ZBTB48	ENST00000319084.9	c.712G>A	p.Glu238Lys	missense_variant	3/3	3		ENSP00000313416.5
ZBTB48	ENST00000435905.5	c.712G>A	p.Glu238Lys	missense_variant	3/3	5		ENSP00000416054.1
ZBTB48	ENST00000488936.1	c.-24G>A		5_prime_UTR_variant	2/7	3		ENSP00000466390.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727208

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.712G>A (p.E238K) alteration is located in exon 3 (coding exon 2) of the ZBTB48 gene. This alteration results from a G to A substitution at nucleotide position 712, causing the glutamic acid (E) at amino acid position 238 to be replaced by a lysine (K). 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	0.20
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.077	.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.011	D;D;D
Sift4G	Pathogenic	0.0	D;D;T
Polyphen		0.97	.;.;D
Vest4		0.43
MutPred		0.43		Gain of methylation at E238 (P = 0.0073);Gain of methylation at E238 (P = 0.0073);Gain of methylation at E238 (P = 0.0073);
MVP		0.10
MPC		0.63
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6642139;