11-130238482-C-T

Variant names:

• chr11-130238482-C-T
• rs1954209188
• NM_001301098.2:c.1229G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001301098.2(ZBTB44):​c.1229G>A​(p.Arg410His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZBTB44 NM_001301098.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

Genes affected

ZBTB44 (HGNC:25001): (zinc finger and BTB domain containing 44) Predicted to enable DNA binding activity and metal ion binding activity. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB44	NM_001301098.2	c.1229G>A	p.Arg410His	missense_variant	Exon 4 of 8	ENST00000357899.9	NP_001288027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB44	ENST00000357899.9	c.1229G>A	p.Arg410His	missense_variant	Exon 4 of 8	1	NM_001301098.2	ENSP00000350574.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456298 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723738

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1229G>A (p.R410H) alteration is located in exon 4 (coding exon 3) of the ZBTB44 gene. This alteration results from a G to A substitution at nucleotide position 1229, causing the arginine (R) at amino acid position 410 to be replaced by a histidine (H). 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	0.94
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.011	.;.;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D;.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	.;N;.;.;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.53	T;D;D;D;D
Sift4G	Uncertain	0.019	.;D;T;T;T
Polyphen		1.0, 1.0	.;D;.;.;D
Vest4		0.53, 0.54, 0.54, 0.55
MutPred		0.70		Loss of MoRF binding (P = 0.0144);Loss of MoRF binding (P = 0.0144);Loss of MoRF binding (P = 0.0144);Loss of MoRF binding (P = 0.0144);Loss of MoRF binding (P = 0.0144);
MVP		0.47
MPC		1.4
ClinPred		0.96	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64

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: rs1954209188; hg19: chr11-130108377;