Variant 16-727596-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032304.4(HAGHL):c.87C>A(p.Asp29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HAGHL
NM_032304.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.63

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 made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAGHL	NM_032304.4 linkuse as main transcript	c.87C>A	p.Asp29Glu	missense_variant	1/8	ENST00000389703.8	NP_115680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAGHL	ENST00000389703.8 linkuse as main transcript	c.87C>A	p.Asp29Glu	missense_variant	1/8	1	NM_032304.4	ENSP00000374353	P1	Q6PII5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000414

AC:

AN:

241744

Hom.:

AF XY:

0.00000758

AC XY:

AN XY:

131878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

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:

6.86e-7

AC:

AN:

1457818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000831

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

Mar 28, 2023

The c.87C>A (p.D29E) alteration is located in exon 1 (coding exon 1) of the HAGHL gene. This alteration results from a C to A substitution at nucleotide position 87, causing the aspartic acid (D) at amino acid position 29 to be replaced by a glutamic acid (E). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;.;.;T;T;.;T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.82

.;T;T;T;T;D;D;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;H;H;.;.;.;H;.;.

MutationTaster

Benign

0.75

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D;D;.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Polyphen

0.66

P;D;P;.;D;.;D;.;.

Vest4

0.81

MutPred

0.96

Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);Gain of ubiquitination at K34 (P = 0.1084);

MVP

0.71

MPC

0.70

ClinPred

1.0

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.75

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