1-32592995-G-A

Position:

• chr1-32592995-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001040441.3(ZBTB8A):​c.64G>A​(p.Val22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,106 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: ZBTB8A NM_001040441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09306538).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB8A	NM_001040441.3	c.64G>A	p.Val22Ile	missense_variant	3/5	ENST00000373510.9	NP_001035531.2
ZBTB8A	NM_001291496.2	c.64G>A	p.Val22Ile	missense_variant	3/5		NP_001278425.1
ZBTB8A	NR_111980.2	n.229-2059G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB8A	ENST00000373510.9	c.64G>A	p.Val22Ile	missense_variant	3/5	1	NM_001040441.3	ENSP00000362609.3
ZBTB8A	ENST00000316459.4	c.64G>A	p.Val22Ile	missense_variant	3/5	1		ENSP00000317561.4
ENSG00000254553	ENST00000480336.1	n.*183G>A		non_coding_transcript_exon_variant	8/10	2		ENSP00000455300.1
ENSG00000254553	ENST00000480336.1	n.*183G>A		3_prime_UTR_variant	8/10	2		ENSP00000455300.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152222 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 72 AN: 251294 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135800

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000436 AC: 638 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000510

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152222 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74366

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000558

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.000230

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000474

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

Nov 08, 2022

The c.64G>A (p.V22I) alteration is located in exon 3 (coding exon 1) of the ZBTB8A gene. This alteration results from a G to A substitution at nucleotide position 64, causing the valine (V) at amino acid position 22 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	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.63	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.10
Sift	Benign	0.36	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.022	.;B
Vest4		0.28
MVP		0.63
MPC		0.49
ClinPred		0.025	T
GERP RS		5.3
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150478201; hg19: chr1-33058596;