14-64522253-A-G

Variant names:

• chr14-64522253-A-G
• rs2079867434
• NM_001123329.2:c.749A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001123329.2(ZBTB1):​c.749A>G​(p.Tyr250Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZBTB1 NM_001123329.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 0 publications found

Genes affected

ZBTB1 (HGNC:20259): (zinc finger and BTB domain containing 1) Enables K63-linked polyubiquitin modification-dependent protein binding activity; protein heterodimerization activity; and protein homodimerization activity. Involved in several processes, including cellular response to UV; nucleobase-containing compound biosynthetic process; and protein homooligomerization. Located in centrosome; nuclear body; and nuclear membrane. [provided by Alliance of Genome Resources, Apr 2022]

HSPA2-AS1 (HGNC:55433): (HSPA2 and ZBTB1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24886176).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001123329.2. 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
	ZBTB1	NM_001123329.2	MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 2 of 2	NP_001116801.1	Q9Y2K1-1
	ZBTB1	NM_001438534.1		c.749A>G	p.Tyr250Cys	missense	Exon 5 of 5	NP_001425463.1
	ZBTB1	NM_014950.3		c.749A>G	p.Tyr250Cys	missense	Exon 2 of 3	NP_055765.2	Q9Y2K1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB1	ENST00000683701.1	MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 2 of 2	ENSP00000506911.1	Q9Y2K1-1
	ZBTB1	ENST00000554015.5	TSL:1	c.749A>G	p.Tyr250Cys	missense	Exon 4 of 4	ENSP00000451000.1	Q9Y2K1-1
	ZBTB1	ENST00000358738.3	TSL:1	c.749A>G	p.Tyr250Cys	missense	Exon 2 of 3	ENSP00000351587.3	Q9Y2K1-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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	Benign	0.073
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0062	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.19	T
Polyphen		0.95	P
Vest4		0.40
MutPred		0.63		Loss of MoRF binding (P = 0.144)
MVP		0.15
ClinPred		0.72	D
GERP RS		2.1
Varity_R		0.073
gMVP		0.22
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs2079867434; hg19: chr14-64988971;