16-1809791-C-T

Variant names:

• chr16-1809791-C-T
• rs749840672
• NM_005326.6:c.790G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001286249.2(HAGH):​c.681G>A​(p.Trp227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HAGH NM_001286249.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.519
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286249.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGH	NM_005326.6	MANE Select	c.790G>A	p.Ala264Thr	missense	Exon 8 of 9	NP_005317.2	Q16775-1
	HAGH	NM_001286249.2		c.681G>A	p.Trp227*	stop_gained	Exon 7 of 8	NP_001273178.1	Q16775-3
	HAGH	NM_001363912.1		c.790G>A	p.Ala264Thr	missense	Exon 8 of 9	NP_001350841.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGH	ENST00000397356.8	TSL:1 MANE Select	c.790G>A	p.Ala264Thr	missense	Exon 8 of 9	ENSP00000380514.3	Q16775-1
	HAGH	ENST00000455446.6	TSL:2	c.681G>A	p.Trp227*	stop_gained	Exon 7 of 8	ENSP00000406552.2	Q16775-3
	HAGH	ENST00000945501.1		c.829G>A	p.Ala277Thr	missense	Exon 8 of 9	ENSP00000615560.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251392 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.84e-7 AC: 1 AN: 1461608 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111764

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

African (AFR) AF: 0.0000965 AC: 4 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.00066
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.61	T
PhyloP100		0.52
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Benign	0.042	D
Sift4G	Benign	0.16	T
Polyphen		0.60	P
Vest4		0.48
MutPred		0.34		Gain of phosphorylation at A264 (P = 0.0647)
MVP		0.88
MPC		0.060
ClinPred		0.62	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.65
Mutation Taster		=133/67	polymorphism

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

Other links and lift over

dbSNP: rs749840672; hg19: chr16-1859792;