Variant 6-138404538-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014320.3(HEBP2):c.43G>A(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,300,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

HEBP2
NM_014320.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.910

Variant links:

Genes affected

HEBP2 (HGNC:15716): (heme binding protein 2) The protein encoded by this gene is found predominately in the cytoplasm, where it plays a role in the collapse of mitochondrial membrane potential (MMP) prior to necrotic cell death. The encoded protein enhances outer and inner mitochondrial membrane permeabilization, especially under conditions of oxidative stress. [provided by RefSeq, May 2016]

HEBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06203282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEBP2	NM_014320.3 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	1/4	ENST00000607197.6	NP_055135.1	Q9Y5Z4-1
HEBP2	NM_001326381.2 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	1/4		NP_001313310.1	Q5THN1
HEBP2	NM_001326380.2 linkuse as main transcript	c.136-607G>A		intron_variant			NP_001313309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HEBP2	ENST00000607197.6 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	1/4	1	NM_014320.3	ENSP00000475750.1	Q9Y5Z4-1
HEBP2	ENST00000367697.7 linkuse as main transcript	c.43G>A	p.Ala15Thr	missense_variant	1/4	2		ENSP00000356670.3	Q5THN1
HEBP2	ENST00000448741.5 linkuse as main transcript	c.136-607G>A		intron_variant		5		ENSP00000392101.1	C9IZA0

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

150276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

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:

0.000193

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

130

AN:

1149920

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

555592

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000257

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000246

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.000195

GnomAD4 genome

AF:

0.000106

AC:

AN:

150276

Hom.:

Cov.:

AF XY:

0.0000954

AC XY:

AN XY:

73390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000198

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000193

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000128

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.43G>A (p.A15T) alteration is located in exon 1 (coding exon 1) of the HEBP2 gene. This alteration results from a G to A substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a threonine (T). 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

Benign

0.088

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

3.5

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.25

.;N

REVEL

Benign

0.013

Sift

Uncertain

0.011

.;D

Sift4G

Benign

0.18

T;T

Polyphen

0.033

B;.

Vest4

0.13

MutPred

0.31

Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);

MVP

0.030

MPC

0.044

ClinPred

0.053

GERP RS

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.096

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over