6-136268287-G-T

Variant names:

• chr6-136268287-G-T
• rs77081633
• NM_014739.3:c.2272C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.03
• Publications: 14 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• 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 Benign. ClinVar VariationId is 402421.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014739.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCLAF1	NM_014739.3	MANE Select	c.2272C>A	p.Pro758Thr	missense	Exon 10 of 13	NP_055554.1	Q9NYF8-1
	BCLAF1	NM_001386700.1		c.2272C>A	p.Pro758Thr	missense	Exon 11 of 14	NP_001373629.1	Q9NYF8-1
	BCLAF1	NM_001386701.1		c.2272C>A	p.Pro758Thr	missense	Exon 11 of 14	NP_001373630.1	Q9NYF8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCLAF1	ENST00000531224.6	TSL:1 MANE Select	c.2272C>A	p.Pro758Thr	missense	Exon 10 of 13	ENSP00000435210.1	Q9NYF8-1
	BCLAF1	ENST00000527759.5	TSL:1	c.2266C>A	p.Pro756Thr	missense	Exon 10 of 13	ENSP00000434826.1	Q9NYF8-2
	BCLAF1	ENST00000530767.5	TSL:1	c.1753C>A	p.Pro585Thr	missense	Exon 10 of 13	ENSP00000436501.1	Q9NYF8-4

Frequencies

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

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

GnomAD2 exomes AF: 0.0671 AC: 15579 AN: 232134 AF XY: 0.0693

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000489 AC: 16 AN: 32752

American (AMR) AF: 0.00182 AC: 77 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 43 AN: 25266

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00117 AC: 98 AN: 83530

European-Finnish (FIN) AF: 0.00152 AC: 79 AN: 51994

Middle Eastern (MID) AF: 0.00166 AC: 9 AN: 5432

European-Non Finnish (NFE) AF: 0.00332 AC: 3478 AN: 1046364

Other (OTH) AF: 0.00214 AC: 124 AN: 57846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67796

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.117 Hom.: 1306

ExAC AF: 0.100 AC: 12147

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	BCLAF1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.046
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.25	T
Polyphen		0.042	B
Vest4		0.26
ClinPred		0.016	T
GERP RS		3.7
Varity_R		0.068
gMVP		0.065
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

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