4-4303022-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_145291.4(ZBTB49):c.1186G>A(p.Ala396Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,613,982 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A396V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (102 hom.)
• Consequence: ZBTB49 NM_145291.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.939

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0083274245).
• BP6: Variant 4-4303022-G-A is Benign according to our data. Variant chr4-4303022-G-A is described in ClinVar as [Benign]. Clinvar id is 777803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB49	NM_145291.4	c.1186G>A	p.Ala396Thr	missense_variant	3/8	ENST00000337872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB49	ENST00000337872.9	c.1186G>A	p.Ala396Thr	missense_variant	3/8	1	NM_145291.4	P1

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00735 AC: 1841 AN: 250396 Hom.: 10 AF XY: 0.00726 AC XY: 985 AN XY: 135618

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.00896

Gnomad ASJ exome AF: 0.00834

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0108 AC: 15779 AN: 1461712 Hom.: 102 Cov.: 34 AF XY: 0.0104 AC XY: 7560 AN XY: 727142

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00954

Gnomad4 ASJ exome AF: 0.00819

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00686 AC: 1044 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74452

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0106 Hom.: 11

Bravo AF: 0.00794

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00712 AC: 864

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.1
Dann	Benign	0.73
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.060	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.019
Sift	Benign	0.52	T
Sift4G	Benign	0.73	T
Polyphen		0.0080	B
Vest4		0.043
MVP		0.21
MPC		0.15
ClinPred		0.0035	T
GERP RS		3.6
Varity_R		0.021
gMVP		0.085

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

Publications

LitVar

Other links and lift over

dbSNP: rs114306264; hg19: chr4-4304749; COSMIC: COSV100552329; COSMIC: COSV100552329;