Genetic Variant HRK:p.Met49Lys (chr12-116881162-A-T) – 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>A(p.Met49Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,025,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). 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: not found (cov: 30)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

HRK
NM_003806.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

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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>A	p.Met49Lys	missense	Exon 1 of 2	NP_003797.1	O00198
	HRK	NR_073189.3		n.280T>A		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>A	p.Met49Lys	missense	Exon 1 of 2	ENSP00000257572.4	O00198
ENSG00000297968	ENST00000752207.1		n.111+2394A>T		intron	N/A
ENSG00000297968	ENST00000752208.1		n.84+2394A>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000195

AC:

AN:

1025874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

486454

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

0.0000496

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:

0.00000113

AC:

AN:

886594

Other (OTH)

AF:

0.00

AC:

AN:

39070

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.055

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.92

PhyloP100

1.5

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.74

Vest4

0.68

MutPred

0.35

Gain of catalytic residue at M49 (P = 0.0028)

MVP

0.088

ClinPred

0.98

GERP RS

3.0

PromoterAI

0.029

Neutral

(source)

Varity_R

0.95

gMVP

0.10

Mutation Taster

=55/45

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

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