Genetic Variant BTF3:p.Gly24Glu (chr5-73498738-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001037637.2(BTF3):c.71G>A(p.Gly24Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,491,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

BTF3
NM_001037637.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Publications

1 publications found

Variant links:

Genes affected

BTF3 (HGNC:1125): (basic transcription factor 3) This gene encodes the basic transcription factor 3. This protein forms a stable complex with RNA polymerase IIB and is required for transcriptional initiation. Alternative splicing results in multiple transcript variants encoding different isoforms. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

BTF3 links:

BTF3-DT (HGNC:55211): (BTF3 divergent transcript)

BTF3-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04610759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTF3	NM_001037637.2 link	c.71G>A	p.Gly24Glu	missense_variant	Exon 1 of 6	ENST00000380591.8	NP_001032726.1	P20290-1
BTF3	NM_001393652.1 link	c.71G>A	p.Gly24Glu	missense_variant	Exon 1 of 5		NP_001380581.1
BTF3	NM_001207.5 link	c.-1+180G>A		intron_variant	Intron 1 of 5		NP_001198.2	P20290-2
BTF3	NM_001393653.1 link	c.-1+180G>A		intron_variant	Intron 1 of 4		NP_001380582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTF3	ENST00000380591.8 link	c.71G>A	p.Gly24Glu	missense_variant	Exon 1 of 6	1	NM_001037637.2	ENSP00000369965.3		P20290-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000222

AC:

AN:

94700

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000341

Gnomad ASJ exome

AF:

0.00141

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

136

AN:

1339398

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

660844

show subpopulations

African (AFR)

AF:

0.0000372

AC:

AN:

26846

American (AMR)

AF:

0.000232

AC:

AN:

21532

Ashkenazi Jewish (ASJ)

AF:

0.000882

AC:

AN:

22672

East Asian (EAS)

AF:

0.00

AC:

AN:

33036

South Asian (SAS)

AF:

0.0000404

AC:

AN:

74216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37628

Middle Eastern (MID)

AF:

0.000627

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.0000912

AC:

AN:

1063202

Other (OTH)

AF:

0.000126

AC:

AN:

55478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000233

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000100

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.71G>A (p.G24E) alteration is located in exon 1 (coding exon 1) of the BTF3 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the glycine (G) at amino acid position 24 to be replaced by a glutamic acid (E). 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

Benign

0.12

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

0.044

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.61

M_CAP

Benign

0.024

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

2.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.10

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.056

Polyphen

0.73

Vest4

0.28

MutPred

0.17

Loss of MoRF binding (P = 0.0436);

MVP

0.32

MPC

1.1

ClinPred

0.20

GERP RS

4.5

PromoterAI

0.073

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.094

Mutation Taster

=89/11

polymorphism

(source)

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

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5-73498738-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over