Genetic Variant BID:p.Asp60Glu (chr22-17743846-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001196.4(BID):c.180T>A(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D60N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BID
NM_001196.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.23

Publications

0 publications found

Variant links:

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]

BID links:

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ACMG classification

Classification was made for transcript

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 link	c.180T>A	p.Asp60Glu	missense_variant	Exon 3 of 6	ENST00000622694.5	NP_001187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BID	ENST00000622694.5 link	c.180T>A	p.Asp60Glu	missense_variant	Exon 3 of 6	1	NM_001196.4	ENSP00000480414.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460336

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

0.087

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

.;T;T;.;T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.73

T;T;.;T;.;T

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.2

.;M;M;M;M;.

PhyloP100

-2.2

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

D;.;D;D;D;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;.;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.96

P;D;D;.;D;.

Vest4

0.74

MutPred

0.90

.;Gain of phosphorylation at S64 (P = 0.1773);Gain of phosphorylation at S64 (P = 0.1773);Gain of phosphorylation at S64 (P = 0.1773);Gain of phosphorylation at S64 (P = 0.1773);Gain of phosphorylation at S64 (P = 0.1773);

MVP

0.36

MPC

0.42

ClinPred

0.97

GERP RS

-5.6

Varity_R

0.63

gMVP

0.56

Mutation Taster

=81/19

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over