10-131970787-C-A

Variant names:

• chr10-131970787-C-A
• NM_004052.4:c.390G>T

Variant summary

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

The NM_004052.4(BNIP3):​c.390G>T​(p.Lys130Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BNIP3 NM_004052.4 missense, splice_region
• Scores: Splicing: ADA: 0.9919
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

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]

PPP2R2D (HGNC:23732): (protein phosphatase 2 regulatory subunit Bdelta) Predicted to enable protein phosphatase regulator activity. Predicted to be involved in exit from mitosis and peptidyl-serine dephosphorylation. Predicted to be part of protein phosphatase type 2A complex. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
BNIP3	NM_004052.4	c.390G>T	p.Lys130Asn	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000368636.9	NP_004043.4
PPP2R2D	XM_047425473.1	c.*1133C>A		3_prime_UTR_variant	Exon 7 of 7		XP_047281429.1
PPP2R2D	XM_006717914.4	c.*1133C>A		3_prime_UTR_variant	Exon 9 of 9		XP_006717977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BNIP3	ENST00000368636.9	c.390G>T	p.Lys130Asn	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_004052.4	ENSP00000357625.6
BNIP3	ENST00000540159.4	c.390G>T	p.Lys130Asn	missense_variant, splice_region_variant	Exon 5 of 5	1		ENSP00000446145.3
BNIP3	ENST00000633835.2	c.390G>T	p.Lys130Asn	missense_variant, splice_region_variant	Exon 5 of 6	3		ENSP00000487769.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.390G>T (p.K130N) alteration is located in exon 5 (coding exon 5) of the BNIP3 gene. This alteration results from a G to T substitution at nucleotide position 390, causing the lysine (K) at amino acid position 130 to be replaced by an asparagine (N). 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	Pathogenic	0.96
BayesDel_addAF	Benign	0.0062	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.46	T
PrimateAI	Uncertain	0.64	T
REVEL	Uncertain	0.39
Sift4G	Benign	0.063	T;T
Vest4		0.75
MVP		0.35
MPC		1.2
ClinPred		0.98	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-133784291;