dbSNP rs1483842843: HRK:p.Met49Arg (chr12-116881162-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_003806.4(HRK):c.146T>G(p.Met49Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,174,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M49V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

HRK
NM_003806.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

Genes affected

HRK (HGNC:5185): (harakiri, BCL2 interacting protein) This gene encodes a member of the BCL-2 protein family. Members of this family are involved in activating or inhibiting apoptosis. The encoded protein localizes to intracellular membranes. This protein promotes apoptosis by interacting with the apoptotic inhibitors BCL-2 and BCL-X(L) via its BH3 domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

HRK links:

ENSG00000297968 (HGNC:):

ENSG00000297968 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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_003806.4. 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
	HRK	NM_003806.4	MANE Select	c.146T>G	p.Met49Arg	missense	Exon 1 of 2	NP_003797.1	O00198
	HRK	NR_073189.3		n.280T>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HRK	ENST00000257572.5	TSL:1 MANE Select	c.146T>G	p.Met49Arg	missense	Exon 1 of 2	ENSP00000257572.4	O00198
ENSG00000297968	ENST00000752207.1		n.111+2394A>C		intron	N/A
ENSG00000297968	ENST00000752208.1		n.84+2394A>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00000673

AC:

AN:

148636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000682

AC:

AN:

1025874

Hom.:

Cov.:

AF XY:

0.00000617

AC XY:

AN XY:

486454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20678

American (AMR)

AF:

0.00

AC:

AN:

6730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11572

East Asian (EAS)

AF:

0.00

AC:

AN:

20164

South Asian (SAS)

AF:

0.00

AC:

AN:

20124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2578

European-Non Finnish (NFE)

AF:

0.00000790

AC:

AN:

886594

Other (OTH)

AF:

0.00

AC:

AN:

39070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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

AF:

0.00000673

AC:

AN:

148636

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72494

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40876

American (AMR)

AF:

0.00

AC:

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

4978

South Asian (SAS)

AF:

0.00

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66900

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.0035

Eigen_PC

Benign

0.00018

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.44

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-0.92

PhyloP100

1.5

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.87

Vest4

0.68

MutPred

0.29

Gain of phosphorylation at T48 (P = 0.0929)

MVP

0.092

ClinPred

0.97

GERP RS

3.0

PromoterAI

0.0086

Neutral

(source)

Varity_R

0.96

gMVP

0.11

Mutation Taster

=54/46

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over