Genetic Variant BNIP3:p.Gly8Trp (chr10-131981785-C-A) – 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_004052.4(BNIP3):c.22G>T(p.Gly8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

BNIP3
NM_004052.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0830

Variant links:

Genes affected

BNIP3 (HGNC:1084): (BCL2 interacting protein 3) This gene is encodes a mitochondrial protein that contains a BH3 domain and acts as a pro-apoptotic factor. The encoded protein interacts with anti-apoptotic proteins, including the E1B 19 kDa protein and Bcl2. This gene is silenced in tumors by DNA methylation. [provided by RefSeq, Dec 2014]

BNIP3 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=0.23421702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BNIP3	NM_004052.4 link	c.22G>T	p.Gly8Trp	missense_variant	Exon 1 of 6	ENST00000368636.9	NP_004043.4	Q12983Q6NVY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BNIP3	ENST00000368636.9 link	c.22G>T	p.Gly8Trp	missense_variant	Exon 1 of 6	1	NM_004052.4	ENSP00000357625.6	Q12983
BNIP3	ENST00000540159.4 link	c.22G>T	p.Gly8Trp	missense_variant	Exon 1 of 5	1		ENSP00000446145.3	B4DHJ7
BNIP3	ENST00000633835.2 link	c.22G>T	p.Gly8Trp	missense_variant	Exon 1 of 6	3		ENSP00000487769.2	A0A0J9YW18
BNIP3	ENST00000631806.1 link	n.181G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.51e-7

AC:

AN:

1331308

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

656866

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27342

American (AMR)

AF:

0.00

AC:

AN:

28744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23510

East Asian (EAS)

AF:

0.00

AC:

AN:

29128

South Asian (SAS)

AF:

0.00

AC:

AN:

73110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4186

European-Non Finnish (NFE)

AF:

9.48e-7

AC:

AN:

1055322

Other (OTH)

AF:

0.00

AC:

AN:

55136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.57

T;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.99

PhyloP100

0.083

PrimateAI

Uncertain

0.75

REVEL

Benign

0.19

Sift4G

Uncertain

0.0060

D;D

Vest4

0.28

MVP

0.33

MPC

1.1

ClinPred

0.75

GERP RS

1.3

PromoterAI

0.10

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.064

gMVP

0.18

Mutation Taster

=91/9

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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10-131981785-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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