22-17738093-A-G

Variant names:

• chr22-17738093-A-G
• rs778228540
• NM_001196.4:c.500T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001196.4(BID):​c.500T>C​(p.Leu167Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BID NM_001196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BID	NM_001196.4	c.500T>C	p.Leu167Pro	missense_variant	Exon 5 of 6	ENST00000622694.5	NP_001187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BID	ENST00000622694.5	c.500T>C	p.Leu167Pro	missense_variant	Exon 5 of 6	1	NM_001196.4	ENSP00000480414.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251492 AF XY: 0.00

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: 0.0000462

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727230

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.000187 AC: 10 AN: 53418

Gnomad4 NFE exome AF: 0.0000270 AC: 30 AN: 1112012

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000942 AC: 0.000094162 AN: 0.000094162

Gnomad4 NFE AF: 0.0000882 AC: 0.0000881834 AN: 0.0000881834

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638T>C (p.L213P) alteration is located in exon 5 (coding exon 5) of the BID gene. This alteration results from a T to C substitution at nucleotide position 638, causing the leucine (L) at amino acid position 213 to be replaced by a proline (P). 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	0.93
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;.;T;.;.;T;.;T;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T;.;T;.;T;.;.;.;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.;M;.;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.4	D;.;.;.;D;D;D;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.;.;.;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;D;.;D;.
Vest4		0.95
MutPred		0.95		.;.;Gain of disorder (P = 0.0148);.;.;Gain of disorder (P = 0.0148);.;Gain of disorder (P = 0.0148);.;
MVP		0.42
MPC		0.90
ClinPred		0.67	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.88
Mutation Taster		=74/26	polymorphism

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: rs778228540; hg19: chr22-18220859;