16-1816945-C-A

Variant names:

• chr16-1816945-C-A
• rs138102620
• NM_005326.6:c.695G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005326.6(HAGH):​c.695G>T​(p.Arg232Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HAGH NM_005326.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 5 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17637187).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005326.6. 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.695G>T	p.Arg232Leu	missense	Exon 7 of 9	NP_005317.2	Q16775-1
	HAGH	NM_001363912.1		c.695G>T	p.Arg232Leu	missense	Exon 7 of 9	NP_001350841.1
	HAGH	NM_001040427.2		c.551G>T	p.Arg184Leu	missense	Exon 8 of 10	NP_001035517.1	Q16775-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGH	ENST00000397356.8	TSL:1 MANE Select	c.695G>T	p.Arg232Leu	missense	Exon 7 of 9	ENSP00000380514.3	Q16775-1
	HAGH	ENST00000945501.1		c.734G>T	p.Arg245Leu	missense	Exon 7 of 9	ENSP00000615560.1
	HAGH	ENST00000851988.1		c.695G>T	p.Arg232Leu	missense	Exon 7 of 10	ENSP00000522047.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461550 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111756

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	19
DANN	Benign	0.89
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.048	D
PhyloP100		1.4
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.049
Sift	Uncertain	0.014	D
Sift4G	Benign	0.075	T
Vest4		0.44
MutPred		0.25		Gain of glycosylation at A196 (P = 0.0017)
MVP		0.50
ClinPred		0.97	D
GERP RS		5.0
PromoterAI		-0.013	Neutral
Varity_R		0.56
Mutation Taster		=34/66	disease causing

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: rs138102620; hg19: chr16-1866946; COSMIC: COSV101272498; COSMIC: COSV101272498;