6-136275677-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014739.3(BCLAF1):c.1707G>C(p.Arg569Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCLAF1 NM_014739.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BCLAF1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCLAF1	NM_014739.3	c.1707G>C	p.Arg569Ser	missense_variant	6/13	ENST00000531224.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCLAF1	ENST00000531224.6	c.1707G>C	p.Arg569Ser	missense_variant	6/13	1	NM_014739.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Dec 30, 2021

The p.R569S variant (also known as c.1707G>C), located in coding exon 4 of the BCLAF1 gene, results from a G to C substitution at nucleotide position 1707. The arginine at codon 569 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;.;.;.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;.;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;D;D;D;.;.
Sift4G	Benign	0.090	T;T;T;T;T;T;T;.
Polyphen		0.53	P;P;.;D;P;P;.;.
Vest4		0.99
MutPred		0.40		Gain of phosphorylation at R569 (P = 0.0532);.;Gain of phosphorylation at R569 (P = 0.0532);.;.;.;Gain of phosphorylation at R569 (P = 0.0532);Gain of phosphorylation at R569 (P = 0.0532);
MVP		0.38
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.53

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: rs773700377; hg19: chr6-136596815;