chr4-4299949-G-A

Position:

• chr4-4299949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145291.4(ZBTB49):​c.4G>A​(p.Asp2Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB49 NM_145291.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36

Genes affected

ZBTB49 (HGNC:19883): (zinc finger and BTB domain containing 49) Enables DNA-binding transcription factor binding activity; sequence-specific DNA binding activity; and transcription coactivator binding activity. Involved in negative regulation of cell population proliferation; positive regulation of transcription by RNA polymerase II; and regulation of cell cycle. Located in cytosol; microtubule cytoskeleton; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB49	NM_145291.4	c.4G>A	p.Asp2Asn	missense_variant	2/8	ENST00000337872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB49	ENST00000337872.9	c.4G>A	p.Asp2Asn	missense_variant	2/8	1	NM_145291.4	P1
ZBTB49	ENST00000515012.5	c.4G>A	p.Asp2Asn	missense_variant, NMD_transcript_variant	2/6	1
ZBTB49	ENST00000503703.5	c.4G>A	p.Asp2Asn	missense_variant, NMD_transcript_variant	2/7	1
ZBTB49	ENST00000502918.1	c.4G>A	p.Asp2Asn	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 01, 2022

The c.4G>A (p.D2N) alteration is located in exon 2 (coding exon 1) of the ZBTB49 gene. This alteration results from a G to A substitution at nucleotide position 4, causing the aspartic acid (D) at amino acid position 2 to be replaced by an asparagine (N). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.093	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.0058	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.23		Loss of glycosylation at T6 (P = 0.066);Loss of glycosylation at T6 (P = 0.066);
MVP		0.91
MPC		0.64
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.43
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1720402052; hg19: chr4-4301676;