6-136268287-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BP6_Very_Strong

The NM_014739.3(BCLAF1):c.2272C>A(p.Pro758Thr) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P758S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BCLAF1 NM_014739.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BCLAF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023156106).
• BP6: Variant 6-136268287-G-T is Benign according to our data. Variant chr6-136268287-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 402421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCLAF1	NM_014739.3	c.2272C>A	p.Pro758Thr	missense_variant	10/13	ENST00000531224.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCLAF1	ENST00000531224.6	c.2272C>A	p.Pro758Thr	missense_variant	10/13	1	NM_014739.3	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151776 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0671 AC: 15579 AN: 232134 Hom.: 0 AF XY: 0.0693 AC XY: 8691 AN XY: 125338

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.00262

Gnomad SAS exome AF: 0.0384

Gnomad FIN exome AF: 0.0750

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0703

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00283 AC: 3924 AN: 1384952 Hom.: 0 Cov.: 31 AF XY: 0.00323 AC XY: 2227 AN XY: 689630

Gnomad4 AFR exome AF: 0.000489

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151776 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74104

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.113 Hom.: 545

ExAC AF: 0.100 AC: 12147

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

BCLAF1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Benign	0.79
DEOGEN2	Benign	0.066	T;.;.;.;.;.
Eigen	Benign	-0.089
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T;T;T;T;T;.
MetaRNN	Benign	0.0023	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
MutationTaster	Benign	0.90	D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.046
Sift	Uncertain	0.0090	D;D;D;D;D;D
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.042	B;B;.;B;B;B
Vest4		0.26
ClinPred		0.016	T
GERP RS		3.7
Varity_R		0.068
gMVP		0.065

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: rs77081633; hg19: chr6-136589425; COSMIC: COSV50356877; COSMIC: COSV50356877;