3-101651654-C-T

Variant names:

• chr3-101651654-C-T
• rs769515266
• NM_014415.4:c.2674G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014415.4(ZBTB11):​c.2674G>A​(p.Gly892Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,814 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: 0.0000021 (0 hom.)
• Consequence: ZBTB11 NM_014415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

ZBTB11 (HGNC:16740): (zinc finger and BTB domain containing 11) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in nucleoplasm. Implicated in autosomal recessive non-syndromic intellectual disability. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB11	NM_014415.4	c.2674G>A	p.Gly892Arg	missense_variant	Exon 11 of 11	ENST00000312938.5	NP_055230.2
ZBTB11	XM_011512689.3	c.2479G>A	p.Gly827Arg	missense_variant	Exon 11 of 11		XP_011510991.1
ZBTB11	XM_011512690.3	c.1822G>A	p.Gly608Arg	missense_variant	Exon 9 of 9		XP_011510992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB11	ENST00000312938.5	c.2674G>A	p.Gly892Arg	missense_variant	Exon 11 of 11	1	NM_014415.4	ENSP00000326200.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000137 AC: 3 AN: 218668 Hom.: 0 AF XY: 0.00000844 AC XY: 1 AN XY: 118456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000177

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419814 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 702586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2674G>A (p.G892R) alteration is located in exon 11 (coding exon 11) of the ZBTB11 gene. This alteration results from a G to A substitution at nucleotide position 2674, causing the glycine (G) at amino acid position 892 to be replaced by an arginine (R). 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	0.89
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.86		Gain of MoRF binding (P = 0.0152);
MVP		0.57
MPC		2.1
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.81

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: rs769515266; hg19: chr3-101370498;