12-116881162-A-T

Position:

• chr12-116881162-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: HRK NM_003806.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRK	NM_003806.4	c.146T>A	p.Met49Lys	missense_variant	1/2	ENST00000257572.5	NP_003797.1
HRK	NR_073189.3	n.280T>A		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRK	ENST00000257572.5	c.146T>A	p.Met49Lys	missense_variant	1/2	1	NM_003806.4	ENSP00000257572.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000195 AC: 2 AN: 1025874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 486454

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000496

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.146T>A (p.M49K) alteration is located in exon 1 (coding exon 1) of the HRK gene. This alteration results from a T to A substitution at nucleotide position 146, causing the methionine (M) at amino acid position 49 to be replaced by a lysine (K). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.92	T
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.74	P
Vest4		0.68
MutPred		0.35		Gain of catalytic residue at M49 (P = 0.0028);
MVP		0.088
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs1483842843; hg19: chr12-117318967;