6-33455786-C-T

Variant names:

• chr6-33455786-C-T
• rs778944081
• NM_152735.4:c.686C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152735.4(ZBTB9):​c.686C>T​(p.Ala229Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ZBTB9 NM_152735.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

ZBTB9 (HGNC:28323): (zinc finger and BTB domain containing 9) Enables identical protein 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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05508408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB9	NM_152735.4	c.686C>T	p.Ala229Val	missense_variant	Exon 2 of 2	ENST00000395064.3	NP_689948.1
ZBTB9	XM_047418350.1	c.686C>T	p.Ala229Val	missense_variant	Exon 2 of 2		XP_047274306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB9	ENST00000395064.3	c.686C>T	p.Ala229Val	missense_variant	Exon 2 of 2	1	NM_152735.4	ENSP00000378503.2
ZBTB9	ENST00000612407.1	c.268C>T	p.Pro90Ser	missense_variant	Exon 2 of 2	3		ENSP00000478118.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248562 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459666 Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7 AN XY: 726036

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686C>T (p.A229V) alteration is located in exon 2 (coding exon 1) of the ZBTB9 gene. This alteration results from a C to T substitution at nucleotide position 686, causing the alanine (A) at amino acid position 229 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.032
Sift	Benign	0.19	T
Sift4G	Benign	0.34	T
Polyphen		0.022	B
Vest4		0.076
MutPred		0.25		Loss of glycosylation at S228 (P = 0.1119);
MVP		0.21
MPC		0.36
ClinPred		0.039	T
GERP RS		4.4
Varity_R		0.064
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778944081; hg19: chr6-33423563;