16-1816945-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005326.6(HAGH):​c.695G>A​(p.Arg232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,613,866 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (3 hom.)
• Consequence: HAGH NM_005326.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05161199).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAGH	NM_005326.6	c.695G>A	p.Arg232His	missense_variant	Exon 7 of 9	ENST00000397356.8	NP_005317.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAGH	ENST00000397356.8	c.695G>A	p.Arg232His	missense_variant	Exon 7 of 9	1	NM_005326.6	ENSP00000380514.3

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000518 AC: 130 AN: 251118 Hom.: 2 AF XY: 0.000479 AC XY: 65 AN XY: 135822

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000950 AC: 1388 AN: 1461536 Hom.: 3 Cov.: 31 AF XY: 0.000877 AC XY: 638 AN XY: 727108

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000565 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.695G>A (p.R232H) 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 695, causing the arginine (R) at amino acid position 232 to be replaced by a histidine (H). 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	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.030
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	0.44	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.061
Sift	Uncertain	0.012	D
Sift4G	Benign	0.18	T
Vest4		0.38
MVP		0.74
ClinPred		0.080	T
GERP RS		5.0

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

Other links and lift over

dbSNP: rs138102620; hg19: chr16-1866946; COSMIC: COSV68401017; COSMIC: COSV68401017;