NM_014320.3:c.541A>G

Variant names:

• chr6-138413001-A-G
• rs999544529
• NM_014320.3:c.541A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014320.3(HEBP2):​c.541A>G​(p.Ser181Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: HEBP2 NM_014320.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.541A>G	p.Ser181Gly	missense	Exon 4 of 4	NP_055135.1	Q9Y5Z4-1
	HEBP2	NM_001326380.2		c.574A>G	p.Ser192Gly	missense	Exon 4 of 4	NP_001313309.1
	HEBP2	NM_001326381.2		c.*72A>G		3_prime_UTR	Exon 4 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.541A>G	p.Ser181Gly	missense	Exon 4 of 4	ENSP00000475750.1	Q9Y5Z4-1
	HEBP2	ENST00000858693.1		c.775A>G	p.Ser259Gly	missense	Exon 5 of 5	ENSP00000528752.1
	HEBP2	ENST00000448741.5	TSL:5	c.*72A>G		3_prime_UTR	Exon 4 of 4	ENSP00000392101.1	C9IZA0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251218 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.16
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0043	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.3
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.74		Loss of stability (P = 0.063)
MVP		0.20
MPC		0.30
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.78
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs999544529; hg19: chr6-138734138;