6-136278253-C-T

Position:

• chr6-136278253-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP2 BP4_Strong BP6_Very_Strong

The NM_014739.3(BCLAF1):​c.628G>A​(p.Gly210Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000163 in 1,603,494 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: BCLAF1 NM_014739.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.13

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 -9 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=0.0066773593).
• BP6: Variant 6-136278253-C-T is Benign according to our data. Variant chr6-136278253-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 402423.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.628G>A	p.Gly210Ser	missense_variant	4/13	ENST00000531224.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCLAF1	ENST00000531224.6	c.628G>A	p.Gly210Ser	missense_variant	4/13	1	NM_014739.3	P4

Frequencies

GnomAD3 genomes AF: 0.000976 AC: 146 AN: 149540 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00120

Gnomad ASJ AF: 0.000879

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00336

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000491

GnomAD3 exomes AF: 0.0104 AC: 2550 AN: 246102 Hom.: 0 AF XY: 0.0103 AC XY: 1363 AN XY: 132816

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00580

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00233

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0000798 AC: 116 AN: 1453836 Hom.: 0 Cov.: 32 AF XY: 0.0000719 AC XY: 52 AN XY: 723224

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000976 AC: 146 AN: 149658 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 84 AN XY: 73152

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.00120

Gnomad4 ASJ AF: 0.000879

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00336

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000485

Alfa AF: 0.00511 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0201 AC: 2445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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 - 5% MAF in Finnish population. Both parents carry this variant in the heterozygous state - variants in this gene are unlikely to be related to patient phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.;.;.;.;.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;.;D;D
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.74	N;.;.;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N;.;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D;D;D;D;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T;.
Polyphen		1.0	D;D;.;D;D;D;.;.
Vest4		0.53
ClinPred		0.016	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.52

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: rs141173428; hg19: chr6-136599391;