Genetic Variant NM_003806.4:c.146T>C (chr12-116881162-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003806.4(HRK):c.146T>C(p.Met49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000851 in 1,174,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000068 ( 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26815337).

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>C	p.Met49Thr	missense	Exon 1 of 2	NP_003797.1	O00198
	HRK	NR_073189.3		n.280T>C		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>C	p.Met49Thr	missense	Exon 1 of 2	ENSP00000257572.4	O00198
ENSG00000297968	ENST00000752207.1		n.111+2394A>G		intron	N/A
ENSG00000297968	ENST00000752208.1		n.84+2394A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000668

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000682

AC:

AN:

1025872

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

486452

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:

0.000388

AC:

AN:

2578

European-Non Finnish (NFE)

AF:

0.00000677

AC:

AN:

886592

Other (OTH)

AF:

0.00

AC:

AN:

39070

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

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:

0.0000202

AC:

AN:

148748

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40990

American (AMR)

AF:

0.0000667

AC:

AN:

14988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.000202

AC:

AN:

4962

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:

290

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

66890

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Benign

0.21

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.39

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.96

PhyloP100

1.5

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.48

Vest4

0.51

MutPred

0.27

Gain of phosphorylation at M49 (P = 0.0117)

MVP

0.085

ClinPred

0.97

GERP RS

3.0

PromoterAI

0.22

Neutral

(source)

Varity_R

0.89

gMVP

0.040

Mutation Taster

=51/49

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