16-728181-A-G

Variant names:

• chr16-728181-A-G
• rs1301518035
• NM_032304.4:c.236A>G

Variant summary

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

The NM_032304.4(HAGHL):​c.236A>G​(p.Asp79Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,307,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D79A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

Genes affected

HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [provided by Alliance of Genome Resources, Apr 2022]

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_032304.4. 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
	HAGHL	NM_032304.4	MANE Select	c.236A>G	p.Asp79Gly	missense	Exon 3 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.236A>G	p.Asp79Gly	missense	Exon 4 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.236A>G	p.Asp79Gly	missense	Exon 4 of 7	NP_996995.1	Q6PII5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	ENST00000389703.8	TSL:1 MANE Select	c.236A>G	p.Asp79Gly	missense	Exon 3 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.341A>G		non_coding_transcript_exon	Exon 3 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.236A>G	p.Asp79Gly	missense	Exon 4 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1307144 Hom.: 0 Cov.: 34 AF XY: 0.00000156 AC XY: 1 AN XY: 642684

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25716

American (AMR) AF: 0.0000464 AC: 1 AN: 21552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21108

East Asian (EAS) AF: 0.00 AC: 0 AN: 29592

South Asian (SAS) AF: 0.00 AC: 0 AN: 67250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3792

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047616

Other (OTH) AF: 0.00 AC: 0 AN: 54230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.48
Sift	Benign	0.069	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.57		Gain of MoRF binding (P = 0.0302)
MVP		0.48
MPC		0.39
ClinPred		0.91	D
GERP RS		3.7
PromoterAI		0.048	Neutral
Varity_R		0.39
gMVP		0.50

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: rs1301518035; hg19: chr16-778181;