rs77081633

chr6-136268287-G-Achr6-136268287-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P758T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: BCLAF1 NM_014739.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BCLAF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.027041227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCLAF1	NM_014739.3	c.2272C>T	p.Pro758Ser	missense_variant	10/13	ENST00000531224.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCLAF1	ENST00000531224.6	c.2272C>T	p.Pro758Ser	missense_variant	10/13	1	NM_014739.3	P4

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151778 Hom.: 0 Cov.: 32

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: 59 AN: 232134 Hom.: 0 AF XY: 0.000263 AC XY: 33 AN XY: 125338

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.: 0 Cov.: 31 AF XY: 0.000330 AC XY: 232 AN XY: 703422

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: 45 AN: 151896 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74234

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: 41

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

Sep 14, 2021

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	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.039	T;.;.;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;T;T;T;T;.
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.027	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.060	N;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs77081633; hg19: chr6-136589425;