22-17743848-C-T

Position:

• chr22-17743848-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001196.4(BID):​c.178G>A​(p.Asp60Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BID NM_001196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BID	NM_001196.4	c.178G>A	p.Asp60Asn	missense_variant	3/6	ENST00000622694.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BID	ENST00000622694.5	c.178G>A	p.Asp60Asn	missense_variant	3/6	1	NM_001196.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

May 13, 2022

The c.316G>A (p.D106N) alteration is located in exon 3 (coding exon 3) of the BID gene. This alteration results from a G to A substitution at nucleotide position 316, causing the aspartic acid (D) at amino acid position 106 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	0.85
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;T;T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D;.;D;.;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	.;M;M;M;M;.
MutationTaster	Benign	0.75	D;D;D;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D;.
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;.;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.80
MutPred		0.91		.;Loss of phosphorylation at T59 (P = 0.0859);Loss of phosphorylation at T59 (P = 0.0859);Loss of phosphorylation at T59 (P = 0.0859);Loss of phosphorylation at T59 (P = 0.0859);Loss of phosphorylation at T59 (P = 0.0859);
MVP		0.55
MPC		0.68
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr22-18226614;