11-64271798-C-T

Position:

• chr11-64271798-C-T

Variant summary

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

The NM_032989.3(BAD):​c.193G>A​(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000072 in 1,249,688 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: 0.0000072 (0 hom.)
• Consequence: BAD NM_032989.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

BAD (HGNC:936): (BCL2 associated agonist of cell death) The protein encoded by this gene is a member of the BCL-2 family. BCL-2 family members are known to be regulators of programmed cell death. This protein positively regulates cell apoptosis by forming heterodimers with BCL-xL (B-cell lymphoma-extra large) and BCL-2, and reversing their death repressor activity. Proapoptotic activity of this protein is regulated through its phosphorylation. Protein kinases AKT and MAP kinase, as well as protein phosphatase calcineurin were found to be involved in the regulation of this protein. Alternative splicing of this gene results in two transcript variants which encode the same isoform. [provided by RefSeq, Dec 2019]

GPR137 (HGNC:24300): (G protein-coupled receptor 137) Predicted to be involved in several processes, including negative regulation of bone resorption; negative regulation of osteoclast differentiation; and positive regulation of TORC1 signaling. Located in lysosomal membrane. [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/exons	MANE	Protein	UniProt
BAD	NM_032989.3	c.193G>A	p.Gly65Arg	missense_variant	3/4	ENST00000309032.8	NP_116784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAD	ENST00000309032.8	c.193G>A	p.Gly65Arg	missense_variant	3/4	1	NM_032989.3	ENSP00000309103.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000720 AC: 9 AN: 1249688 Hom.: 0 Cov.: 32 AF XY: 0.00000987 AC XY: 6 AN XY: 607686

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: 0.00000496

Gnomad4 OTH exome AF: 0.0000789

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

Mar 01, 2023

The c.193G>A (p.G65R) alteration is located in exon 2 (coding exon 2) of the BAD gene. This alteration results from a G to A substitution at nucleotide position 193, causing the glycine (G) at amino acid position 65 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	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.98	D;D
Vest4		0.33
MutPred		0.61		Gain of methylation at G65 (P = 0.0036);Gain of methylation at G65 (P = 0.0036);
MVP		0.83
MPC		1.2
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.23
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1294670707; hg19: chr11-64039270;