16-728325-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032304.4(HAGHL):c.298A>G(p.Ile100Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2978227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGHL	NM_032304.4	c.298A>G	p.Ile100Val	missense_variant	4/8	ENST00000389703.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGHL	ENST00000389703.8	c.298A>G	p.Ile100Val	missense_variant	4/8	1	NM_032304.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405270 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 695644

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2023

The c.298A>G (p.I100V) alteration is located in exon 4 (coding exon 4) of the HAGHL gene. This alteration results from a A to G substitution at nucleotide position 298, causing the isoleucine (I) at amino acid position 100 to be replaced by a valine (V). 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	0.29
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Benign	0.85
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.52	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.68	N;N;N;.;.;N;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.28	T;T;T;T;T;T;.;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T;T
Polyphen		0.92	P;P;P;.;D;D;.;.;.
Vest4		0.35
MutPred		0.51		Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);Gain of methylation at R103 (P = 0.0955);.;
MVP		0.49
MPC		0.39
ClinPred		0.79	D
GERP RS		3.2
Varity_R		0.15
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs947423137; hg19: chr16-778325;