Variant 16-728330-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032304.4(HAGHL):c.303C>A(p.His101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,561,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

HAGHL
NM_032304.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.210

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09271005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGHL	NM_032304.4 linkuse as main transcript	c.303C>A	p.His101Gln	missense_variant	4/8	ENST00000389703.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGHL	ENST00000389703.8 linkuse as main transcript	c.303C>A	p.His101Gln	missense_variant	4/8	1	NM_032304.4	P1	Q6PII5-2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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

GnomAD3 exomes

AF:

0.0000894

AC:

AN:

167692

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

92354

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000143

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000334

AC:

AN:

1409042

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

697846

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000562

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:

0.0000174

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.000185

ExAC

AF:

0.0000349

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

Sep 20, 2023

The c.303C>A (p.H101Q) alteration is located in exon 4 (coding exon 4) of the HAGHL gene. This alteration results from a C to A substitution at nucleotide position 303, causing the histidine (H) at amino acid position 101 to be replaced by a glutamine (Q). 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

Benign

0.26

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.67

M_CAP

Benign

0.056

MetaRNN

Benign

0.093

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.46

N;N;N;.;.;N;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

N;N;N;N;N;N;.;N;N

REVEL

Benign

0.066

Sift

Benign

0.60

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

Sift4G

Benign

0.54

T;T;T;T;T;T;T;T;T

Polyphen

0.80

P;B;P;.;P;P;.;.;.

Vest4

0.30

MutPred

0.43

Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);Loss of methylation at R103 (P = 0.0671);.;

MVP

0.61

MPC

0.35

ClinPred

0.088

GERP RS

-2.0

Varity_R

0.13

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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