15-40091804-C-T

Variant names:

• chr15-40091804-C-T
• rs555721433
• NM_001003940.2:c.538G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 12/19 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104402095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMF	NM_001003940.2	c.538G>A	p.Gly180Arg	missense_variant	Exon 5 of 5	ENST00000354670.9	NP_001003940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMF	ENST00000354670.9	c.538G>A	p.Gly180Arg	missense_variant	Exon 5 of 5	1	NM_001003940.2	ENSP00000346697.4
BMF	ENST00000561360.5	c.538G>A	p.Gly180Arg	missense_variant	Exon 4 of 4	3		ENSP00000453892.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152194 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000412 AC: 10 AN: 242782 Hom.: 0 AF XY: 0.0000305 AC XY: 4 AN XY: 131104

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 SAS exome AF: 0.0000684

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000398 AC: 58 AN: 1456288 Hom.: 0 Cov.: 31 AF XY: 0.0000318 AC XY: 23 AN XY: 723874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000903

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000588

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000656 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538G>A (p.G180R) alteration is located in exon 5 (coding exon 3) of the BMF gene. This alteration results from a G to A substitution at nucleotide position 538, causing the glycine (G) at amino acid position 180 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.72	.;.;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.092
MutPred		0.52		Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);Gain of solvent accessibility (P = 0.019);.;
MVP		0.37
MPC		0.51
ClinPred		0.67	D
GERP RS		2.7
Varity_R		0.085
gMVP		0.17

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: rs555721433; hg19: chr15-40384005;