1-6587612-G-A

Position:

• chr1-6587612-G-A

Variant summary

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

The NM_005341.4(ZBTB48):​c.1359G>A​(p.Met453Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZBTB48 NM_005341.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB48	NM_005341.4	c.1359G>A	p.Met453Ile	missense_variant	7/11	ENST00000377674.9	NP_005332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB48	ENST00000377674.9	c.1359G>A	p.Met453Ile	missense_variant	7/11	1	NM_005341.4	ENSP00000366902	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461004 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Jan 23, 2024

The c.1359G>A (p.M453I) alteration is located in exon 7 (coding exon 6) of the ZBTB48 gene. This alteration results from a G to A substitution at nucleotide position 1359, causing the methionine (M) at amino acid position 453 to be replaced by an isoleucine (I). 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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.38	T;.
Sift4G	Benign	0.097	T;T
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.32		Loss of disorder (P = 0.0803);.;
MVP		0.30
MPC		1.2
ClinPred		0.89	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.31

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: rs138712402; hg19: chr1-6647672;