NM_032989.3:c.236G>T

Variant names:

• chr11-64271755-C-A
• rs1189823366
• NM_032989.3:c.236G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032989.3(BAD):​c.236G>T​(p.Gly79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000773 in 1,293,342 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: BAD NM_032989.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0870
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032989.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAD	NM_032989.3	MANE Select	c.236G>T	p.Gly79Val	missense	Exon 3 of 4	NP_116784.1	Q92934
	BAD	NM_004322.3		c.236G>T	p.Gly79Val	missense	Exon 2 of 3	NP_004313.1	Q92934
	GPR137	NM_001378078.1		c.-16+1094C>A		intron	N/A	NP_001365007.1	Q96N19-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAD	ENST00000309032.8	TSL:1 MANE Select	c.236G>T	p.Gly79Val	missense	Exon 3 of 4	ENSP00000309103.3	Q92934
	BAD	ENST00000394532.7	TSL:1	c.236G>T	p.Gly79Val	missense	Exon 2 of 3	ENSP00000378040.3	Q92934
	GPR137	ENST00000546139.5	TSL:1	c.3+1094C>A		intron	N/A	ENSP00000445570.1	F5H234

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000990 AC: 1 AN: 101002 AF XY: 0.0000182

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.73e-7 AC: 1 AN: 1293342 Hom.: 0 Cov.: 32 AF XY: 0.00000159 AC XY: 1 AN XY: 630750

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

African (AFR) AF: 0.00 AC: 0 AN: 26762

American (AMR) AF: 0.00 AC: 0 AN: 21342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18366

East Asian (EAS) AF: 0.00 AC: 0 AN: 32044

South Asian (SAS) AF: 0.0000159 AC: 1 AN: 62830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1031306

Other (OTH) AF: 0.00 AC: 0 AN: 52896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.68	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.087
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.59		Loss of catalytic residue at A78 (P = 0.1347)
MVP		0.81
MPC		1.1
ClinPred		0.96	D
GERP RS		-0.16
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.089
Mutation Taster		=129/71	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1189823366; hg19: chr11-64039227;