16-1819898-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005326.6(HAGH):c.431A>C(p.Gln144Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HAGH NM_005326.6 missense, splice_region
• Scores: Splicing: ADA: 0.9881
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24

Genes affected

HAGH (HGNC:4805): (hydroxyacylglutathione hydrolase) The enzyme encoded by this gene is classified as a thiolesterase and is responsible for the hydrolysis of S-lactoyl-glutathione to reduced glutathione and D-lactate. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

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, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGH	NM_005326.6	c.431A>C	p.Gln144Pro	missense_variant, splice_region_variant	4/9	ENST00000397356.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGH	ENST00000397356.8	c.431A>C	p.Gln144Pro	missense_variant, splice_region_variant	4/9	1	NM_005326.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.431A>C (p.Q144P) alteration is located in exon 4 (coding exon 4) of the HAGH gene. This alteration results from a A to C substitution at nucleotide position 431, causing the glutamine (Q) at amino acid position 144 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	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;T;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	0.41	N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.050	D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.61	P;.;B;.;.
Vest4		0.71
MutPred		0.47		Loss of catalytic residue at Q144 (P = 0.0215);Loss of catalytic residue at Q144 (P = 0.0215);.;.;.;
MVP		0.94
MPC		0.16
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.82
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1869899;