6-138405985-A-G

Variant names:

• chr6-138405985-A-G
• rs144965410
• NM_014320.3:c.253A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014320.3(HEBP2):​c.253A>G​(p.Met85Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,611,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: HEBP2 NM_014320.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1470992).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014320.3. 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
	HEBP2	NM_014320.3	MANE Select	c.253A>G	p.Met85Val	missense	Exon 3 of 4	NP_055135.1	Q9Y5Z4-1
	HEBP2	NM_001326380.2		c.286A>G	p.Met96Val	missense	Exon 3 of 4	NP_001313309.1
	HEBP2	NM_001326381.2		c.253A>G	p.Met85Val	missense	Exon 3 of 4	NP_001313310.1	Q5THN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEBP2	ENST00000607197.6	TSL:1 MANE Select	c.253A>G	p.Met85Val	missense	Exon 3 of 4	ENSP00000475750.1	Q9Y5Z4-1
	HEBP2	ENST00000858693.1		c.253A>G	p.Met85Val	missense	Exon 3 of 5	ENSP00000528752.1
	HEBP2	ENST00000448741.5	TSL:5	c.286A>G	p.Met96Val	missense	Exon 3 of 4	ENSP00000392101.1	C9IZA0

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000337 AC: 84 AN: 248960 AF XY: 0.000320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000638

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000336 AC: 490 AN: 1459726 Hom.: 0 Cov.: 31 AF XY: 0.000344 AC XY: 250 AN XY: 725916

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44282

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 85476

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000394 AC: 438 AN: 1111310

Other (OTH) AF: 0.000332 AC: 20 AN: 60324

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74392

African (AFR) AF: 0.0000723 AC: 3 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000709

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.40	B
Vest4		0.50
MVP		0.20
MPC		0.047
ClinPred		0.21	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.74
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144965410; hg19: chr6-138727122;