16-728325-A-C

Variant names:

• chr16-728325-A-C
• rs947423137
• NM_032304.4:c.298A>C

Variant summary

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

The NM_032304.4(HAGHL):​c.298A>C​(p.Ile100Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. I100V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15488726).

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.298A>C	p.Ile100Leu	missense	Exon 4 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.298A>C	p.Ile100Leu	missense	Exon 5 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.298A>C	p.Ile100Leu	missense	Exon 5 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.298A>C	p.Ile100Leu	missense	Exon 4 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.485A>C		non_coding_transcript_exon	Exon 3 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.298A>C	p.Ile100Leu	missense	Exon 5 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405270 Hom.: 0 Cov.: 33 AF XY: 0.00000288 AC XY: 2 AN XY: 695644

African (AFR) AF: 0.00 AC: 0 AN: 31712

American (AMR) AF: 0.00 AC: 0 AN: 38672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 36990

South Asian (SAS) AF: 0.00 AC: 0 AN: 80470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088080

Other (OTH) AF: 0.00 AC: 0 AN: 58396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.65
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.64	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.33	N
REVEL	Benign	0.14
Sift	Benign	0.96	T
Sift4G	Benign	0.86	T
Polyphen		0.27	B
Vest4		0.44
MutPred		0.50		Gain of methylation at R103 (P = 0.1346)
MVP		0.47
MPC		0.39
ClinPred		0.50	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.32
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs947423137; hg19: chr16-778325;