1-32593424-C-T

Position:

• chr1-32593424-C-T

Variant summary

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

The NM_001040441.3(ZBTB8A):​c.493C>T​(p.His165Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZBTB8A NM_001040441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

Genes affected

ZBTB8A (HGNC:24172): (zinc finger and BTB domain containing 8A) Predicted to enable RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000254553 (HGNC:):

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=0.1852279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB8A	NM_001040441.3	c.493C>T	p.His165Tyr	missense_variant	3/5	ENST00000373510.9	NP_001035531.2
ZBTB8A	NM_001291496.2	c.493C>T	p.His165Tyr	missense_variant	3/5		NP_001278425.1
ZBTB8A	NR_111980.2	n.229-1630C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB8A	ENST00000373510.9	c.493C>T	p.His165Tyr	missense_variant	3/5	1	NM_001040441.3	ENSP00000362609.3
ZBTB8A	ENST00000316459.4	c.493C>T	p.His165Tyr	missense_variant	3/5	1		ENSP00000317561.4
ENSG00000254553	ENST00000480336.1	n.*612C>T		non_coding_transcript_exon_variant	8/10	2		ENSP00000455300.1
ENSG00000254553	ENST00000480336.1	n.*612C>T		3_prime_UTR_variant	8/10	2		ENSP00000455300.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000355 Hom.: 0

Bravo AF: 0.00000378

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 26, 2022

The c.493C>T (p.H165Y) alteration is located in exon 3 (coding exon 1) of the ZBTB8A gene. This alteration results from a C to T substitution at nucleotide position 493, causing the histidine (H) at amino acid position 165 to be replaced by a tyrosine (Y). 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	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.11
Sift	Benign	0.28	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.039	.;B
Vest4		0.47
MutPred		0.16		Gain of phosphorylation at H165 (P = 0.0297);Gain of phosphorylation at H165 (P = 0.0297);
MVP		0.25
MPC		0.45
ClinPred		0.56	D
GERP RS		5.4
gMVP		0.50

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: rs1644505084; hg19: chr1-33059025;