Variant 16-728172-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032304.4(HAGHL):c.227T>C(p.Leu76Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,462,968 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: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

HAGHL
NM_032304.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.282

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAGHL	NM_032304.4 linkuse as main transcript	c.227T>C	p.Leu76Pro	missense_variant	3/8	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.227T>C	p.Leu76Pro	missense_variant	3/8	1	NM_032304.4	ENSP00000374353	P1	Q6PII5-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.63e-7

AC:

AN:

1310994

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

644904

show subpopulations

Gnomad4 AFR exome

AF:

0.0000389

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151974

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Apr 04, 2024

The c.227T>C (p.L76P) alteration is located in exon 3 (coding exon 3) of the HAGHL gene. This alteration results from a T to C substitution at nucleotide position 227, causing the leucine (L) at amino acid position 76 to be replaced by a proline (P). 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

0.82

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.62

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

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.84

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

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

1.3

L;L;L;.;.;L;.;.;.

MutationTaster

Benign

0.77

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

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.1

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.022

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

Sift4G

Uncertain

0.034

D;T;D;D;D;D;D;D;D

Polyphen

0.95

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

Vest4

0.46

MutPred

0.80

Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);Loss of stability (P = 0.0147);.;

MVP

0.79

MPC

0.71

ClinPred

0.71

GERP RS

2.3

Varity_R

0.69

gMVP

0.72

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