Variant 6-138406045-A-G 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.313A>G(p.Ile105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HEBP2
NM_014320.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

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=0.02902481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEBP2	NM_014320.3 linkuse as main transcript	c.313A>G	p.Ile105Val	missense_variant	3/4	ENST00000607197.6	NP_055135.1	Q9Y5Z4-1
HEBP2	NM_001326380.2 linkuse as main transcript	c.346A>G	p.Ile116Val	missense_variant	3/4		NP_001313309.1
HEBP2	NM_001326381.2 linkuse as main transcript	c.301+12A>G		intron_variant			NP_001313310.1	Q5THN1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HEBP2	ENST00000607197.6 linkuse as main transcript	c.313A>G	p.Ile105Val	missense_variant	3/4	1	NM_014320.3	ENSP00000475750.1	Q9Y5Z4-1
HEBP2	ENST00000448741.5 linkuse as main transcript	c.334+12A>G		intron_variant		5		ENSP00000392101.1	C9IZA0
HEBP2	ENST00000367697.7 linkuse as main transcript	c.301+12A>G		intron_variant		2		ENSP00000356670.3	Q5THN1
HEBP2	ENST00000453452.1 linkuse as main transcript	n.61+12A>G		intron_variant		3		ENSP00000395958.1	H7C0N7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251478

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000494

AC:

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

Jan 03, 2024

The c.313A>G (p.I105V) alteration is located in exon 3 (coding exon 3) of the HEBP2 gene. This alteration results from a A to G substitution at nucleotide position 313, causing the isoleucine (I) at amino acid position 105 to be replaced by a valine (V). 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

0.099

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0086

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.63

M_CAP

Benign

0.0022

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

PrimateAI

Benign

0.44

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.11

MutPred

0.52

Gain of glycosylation at S101 (P = 0.111);

MVP

0.048

MPC

0.041

ClinPred

0.014

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.31

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