Genetic Variant HAGHL:p.Asp29Glu (chr16-727596-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032304.4(HAGHL):c.87C>G(p.Asp29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HAGHL
NM_032304.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.63

Publications

0 publications found

Variant links:

Genes affected

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

HAGHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032304.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAGHL	NM_032304.4	MANE Select	c.87C>G	p.Asp29Glu	missense	Exon 1 of 8	NP_115680.1	Q6PII5-2
HAGHL	NM_001323636.2		c.87C>G	p.Asp29Glu	missense	Exon 2 of 8	NP_001310565.1
HAGHL	NM_207112.2		c.87C>G	p.Asp29Glu	missense	Exon 2 of 7	NP_996995.1	Q6PII5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HAGHL	ENST00000389703.8	TSL:1 MANE Select	c.87C>G	p.Asp29Glu	missense	Exon 1 of 8	ENSP00000374353.3	Q6PII5-2
HAGHL	ENST00000389701.9	TSL:1	n.192C>G		non_coding_transcript_exon	Exon 1 of 7
HAGHL	ENST00000341413.8	TSL:2	c.87C>G	p.Asp29Glu	missense	Exon 2 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

0.000478

GnomAD2 exomes

AF:

0.00000827

AC:

AN:

241744

AF XY:

0.00000758

show subpopulations

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:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1457818

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39588

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1110386

Other (OTH)

AF:

0.0000166

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000831

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

PhyloP100

-1.6

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.66

Vest4

0.81

MutPred

0.96

Gain of ubiquitination at K34 (P = 0.1084)

MVP

0.71

MPC

0.70

ClinPred

1.0

GERP RS

-3.3

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.72

gMVP

0.75

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over