16-1816981-C-T

Position:

• chr16-1816981-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005326.6(HAGH):​c.659G>A​(p.Gly220Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,996 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HAGH NM_005326.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAGH	NM_005326.6	c.659G>A	p.Gly220Asp	missense_variant	7/9	ENST00000397356.8	NP_005317.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAGH	ENST00000397356.8	c.659G>A	p.Gly220Asp	missense_variant	7/9	1	NM_005326.6	ENSP00000380514.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457996 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725712

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 05, 2024

The c.659G>A (p.G220D) alteration is located in exon 7 (coding exon 7) of the HAGH gene. This alteration results from a G to A substitution at nucleotide position 659, causing the glycine (G) at amino acid position 220 to be replaced by an aspartic acid (D). 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	1.0
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	1.0	D
PROVEAN	Benign	0.040	N
REVEL	Benign	0.15
Sift	Benign	0.29	T
Sift4G	Benign	0.14	T
Vest4		0.52
MutPred		0.30		Gain of glycosylation at A184 (P = 0.0012);
MVP		0.76
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1866982;