Genetic Variant NM_014739.3:c.2272C>T (chr6-136268287-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014739.3(BCLAF1):c.2272C>T(p.Pro758Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000307 in 1,564,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

BCLAF1
NM_014739.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

BCLAF1 (HGNC:16863): (BCL2 associated transcription factor 1) This gene encodes a transcriptional repressor that interacts with several members of the BCL2 family of proteins. Overexpression of this protein induces apoptosis, which can be suppressed by co-expression of BCL2 proteins. The protein localizes to dot-like structures throughout the nucleus, and redistributes to a zone near the nuclear envelope in cells undergoing apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

BCLAF1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027041227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCLAF1	NM_014739.3 link	c.2272C>T	p.Pro758Ser	missense_variant	Exon 10 of 13	ENST00000531224.6	NP_055554.1	Q9NYF8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCLAF1	ENST00000531224.6 link	c.2272C>T	p.Pro758Ser	missense_variant	Exon 10 of 13	1	NM_014739.3	ENSP00000435210.1		Q9NYF8-1

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

151778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000354

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000254

AC:

AN:

232134

Hom.:

AF XY:

0.000263

AC XY:

AN XY:

125338

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000275

Gnomad ASJ exome

AF:

0.000528

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.000358

GnomAD4 exome

AF:

0.000308

AC:

435

AN:

1412628

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

232

AN XY:

703422

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.000236

Gnomad4 ASJ exome

AF:

0.00114

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.000274

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000316

Gnomad4 OTH exome

AF:

0.000410

GnomAD4 genome

AF:

0.000296

AC:

AN:

151896

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000354

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000970

Hom.:

545

Bravo

AF:

0.000291

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2272C>T (p.P758S) alteration is located in exon 10 (coding exon 8) of the BCLAF1 gene. This alteration results from a C to T substitution at nucleotide position 2272, causing the proline (P) at amino acid position 758 to be replaced by a serine (S). 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

0.078

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.039

T;.;.;.;.;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.83

T;T;T;T;T;.

M_CAP

Benign

0.0084

MetaRNN

Benign

0.027

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.060

N;.;.;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.22

N;N;N;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.89

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;B;B

Vest4

0.30

MutPred

0.39

Gain of phosphorylation at P758 (P = 0);.;Gain of phosphorylation at P758 (P = 0);.;.;.;

MVP

0.31

ClinPred

0.021

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.049

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over