Genetic Variant HAGHL:p.Pro125Gln (chr16-728401-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032304.4(HAGHL):c.374C>A(p.Pro125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P125R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HAGHL
NM_032304.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0950

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16058147).

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.374C>A	p.Pro125Gln	missense	Exon 4 of 8	NP_115680.1	Q6PII5-2
HAGHL	NM_001323636.2		c.374C>A	p.Pro125Gln	missense	Exon 5 of 8	NP_001310565.1
HAGHL	NM_207112.2		c.374C>A	p.Pro125Gln	missense	Exon 5 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.374C>A	p.Pro125Gln	missense	Exon 4 of 8	ENSP00000374353.3	Q6PII5-2
HAGHL	ENST00000389701.9	TSL:1	n.561C>A		non_coding_transcript_exon	Exon 3 of 7
HAGHL	ENST00000341413.8	TSL:2	c.374C>A	p.Pro125Gln	missense	Exon 5 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1414818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700760

African (AFR)

AF:

0.00

AC:

AN:

32356

American (AMR)

AF:

0.00

AC:

AN:

40076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.00

AC:

AN:

37810

South Asian (SAS)

AF:

0.00

AC:

AN:

81082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5230

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091694

Other (OTH)

AF:

0.00

AC:

AN:

58700

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.28

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.84

M_CAP

Benign

0.0096

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.0

PhyloP100

-0.095

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.8

REVEL

Benign

0.12

Sift

Benign

0.17

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.24

MutPred

0.42

Gain of sheet (P = 0.1451)

MVP

0.38

MPC

0.64

ClinPred

0.58

GERP RS

-4.4

Varity_R

0.057

gMVP

0.16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over