chr3-101651654-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

ZBTB11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal recessive 69

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB11	NM_014415.4	MANE Select	c.2674G>A	p.Gly892Arg	missense	Exon 11 of 11	NP_055230.2	O95625

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB11	ENST00000312938.5	TSL:1 MANE Select	c.2674G>A	p.Gly892Arg	missense	Exon 11 of 11	ENSP00000326200.4	O95625
	ZBTB11	ENST00000704111.1		c.2428G>A	p.Gly810Arg	missense	Exon 10 of 10	ENSP00000515702.1	A0A994J7A5
	ZBTB11	ENST00000688910.1		c.2272G>A	p.Gly758Arg	missense	Exon 11 of 11	ENSP00000510736.1	A0A8I5KRR0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000137 AC: 3 AN: 218668 AF XY: 0.00000844

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31686

American (AMR) AF: 0.00 AC: 0 AN: 37682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24112

East Asian (EAS) AF: 0.0000769 AC: 3 AN: 39024

South Asian (SAS) AF: 0.00 AC: 0 AN: 79666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091708

Other (OTH) AF: 0.00 AC: 0 AN: 58404

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.5
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
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs769515266; hg19: chr3-101370498;