NM_001196.4:c.308C>A

Variant names:

• chr22-17739404-G-T
• rs575351241
• NM_001196.4:c.308C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001196.4(BID):​c.308C>A​(p.Pro103Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P103L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BID NM_001196.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.407
• Publications: 0 publications found

Genes affected

BID (HGNC:1050): (BH3 interacting domain death agonist) This gene encodes a death agonist that heterodimerizes with either agonist BAX or antagonist BCL2, and thus regulate apoptosis. The encoded protein is a member of the BCL-2 family of cell death regulators. It is a mediator of mitochondrial damage induced by caspase-8 (CASP8); CASP8 cleaves this encoded protein, and the COOH-terminal part translocates to mitochondria where it triggers cytochrome c release. Multiple alternatively spliced transcript variants have been found. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3533753).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001196.4. 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
	BID	NM_001196.4	MANE Select	c.308C>A	p.Pro103Gln	missense	Exon 4 of 6	NP_001187.1	A8ASI8
	BID	NM_197966.3		c.446C>A	p.Pro149Gln	missense	Exon 4 of 6	NP_932070.1	P55957-2
	BID	NM_001244567.1		c.308C>A	p.Pro103Gln	missense	Exon 4 of 6	NP_001231496.1	A8ASI8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BID	ENST00000622694.5	TSL:1 MANE Select	c.308C>A	p.Pro103Gln	missense	Exon 4 of 6	ENSP00000480414.1	P55957-1
	BID	ENST00000317361.11	TSL:1	c.446C>A	p.Pro149Gln	missense	Exon 4 of 6	ENSP00000318822.7	P55957-2
	BID	ENST00000551952.5	TSL:1	c.308C>A	p.Pro103Gln	missense	Exon 4 of 6	ENSP00000449236.1	P55957-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458528 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725638

⚠️ 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: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111590

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ 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.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.41
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.081
Sift	Benign	0.036	D
Sift4G	Benign	0.22	T
Polyphen		0.34	B
Vest4		0.26
MutPred		0.74		Gain of helix (P = 0.0078)
MVP		0.32
MPC		0.55
ClinPred		0.85	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.26
Mutation Taster		=81/19	polymorphism

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: rs575351241; hg19: chr22-18222170;