Genetic Variant NM_001003940.2:c.538G>A (chr15-40091804-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001003940.2(BMF):c.538G>A(p.Gly180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,608,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

BMF
NM_001003940.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84

Publications

0 publications found

Variant links:

Genes affected

BMF (HGNC:24132): (Bcl2 modifying factor) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein contains a single BCL2 homology domain 3 (BH3), and has been shown to bind BCL2 proteins and function as an apoptotic activator. This protein is found to be sequestered to myosin V motors by its association with dynein light chain 2, which may be important for sensing intracellular damage and triggering apoptosis. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

BMF links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.104402095).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003940.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMF	NM_001003940.2	MANE Select	c.538G>A	p.Gly180Arg	missense	Exon 5 of 5	NP_001003940.1	Q96LC9-1
BMF	NM_001398495.1		c.538G>A	p.Gly180Arg	missense	Exon 5 of 5	NP_001385424.1	Q96LC9-1
BMF	NM_001398496.1		c.538G>A	p.Gly180Arg	missense	Exon 4 of 4	NP_001385425.1	Q96LC9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMF	ENST00000354670.9	TSL:1 MANE Select	c.538G>A	p.Gly180Arg	missense	Exon 5 of 5	ENSP00000346697.4	Q96LC9-1
BMF	ENST00000397573.5	TSL:1	c.538G>A	p.Gly180Arg	missense	Exon 4 of 4	ENSP00000380703.1	Q96LC9-1
BMF	ENST00000561282.5	TSL:1	c.538G>A	p.Gly180Arg	missense	Exon 4 of 4	ENSP00000453522.1	Q96LC9-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000412

AC:

AN:

242782

AF XY:

0.0000305

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000883

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000555

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1456288

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

723874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.0000903

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39538

South Asian (SAS)

AF:

0.0000588

AC:

AN:

85012

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4866

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1109886

Other (OTH)

AF:

0.0000665

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41566

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000656

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.72

M_CAP

Benign

0.014

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

PhyloP100

1.8

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.14

Sift

Benign

0.25

Sift4G

Benign

0.66

Polyphen

1.0

Vest4

0.092

MutPred

0.52

Gain of solvent accessibility (P = 0.019)

MVP

0.37

MPC

0.51

ClinPred

0.67

GERP RS

2.7

Varity_R

0.085

gMVP

0.17

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over