chr8-26391265-G-A

Position:

• chr8-26391265-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004331.3(BNIP3L):​c.123G>A​(p.Met41Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BNIP3L NM_004331.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

Genes affected

BNIP3L (HGNC:1085): (BCL2 interacting protein 3 like) This gene encodes a protein that belongs to the pro-apoptotic subfamily within the Bcl-2 family of proteins. The encoded protein binds to Bcl-2 and possesses the BH3 domain. The protein directly targets mitochondria and causes apoptotic changes, including loss of membrane potential and the release of cytochrome c. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BNIP3L	NM_004331.3	c.123G>A	p.Met41Ile	missense_variant	2/6	ENST00000380629.7	NP_004322.1
BNIP3L	NM_001330491.2	c.3G>A	p.Met1?	start_lost	2/6		NP_001317420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BNIP3L	ENST00000380629.7	c.123G>A	p.Met41Ile	missense_variant	2/6	1	NM_004331.3	ENSP00000370003	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457574 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 31, 2024

The c.123G>A (p.M41I) alteration is located in exon 2 (coding exon 2) of the BNIP3L gene. This alteration results from a G to A substitution at nucleotide position 123, causing the methionine (M) at amino acid position 41 to be replaced by an isoleucine (I). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;.;.;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T;T;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.27	T;T;D;D;D
Polyphen		0.48	P;.;.;.;.
Vest4		0.33
MutPred		0.50		Loss of catalytic residue at V37 (P = 0.0279);.;.;.;.;
MVP		0.43
MPC		0.31
ClinPred		0.89	D
GERP RS		6.2
Varity_R		0.30
gMVP		0.33

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: rs1243069267; hg19: chr8-26248781;