chr16-728352-G-C

Position:

• chr16-728352-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032304.4(HAGHL):​c.325G>C​(p.Gly109Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAGHL	NM_032304.4	c.325G>C	p.Gly109Arg	missense_variant	4/8	ENST00000389703.8	NP_115680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAGHL	ENST00000389703.8	c.325G>C	p.Gly109Arg	missense_variant	4/8	1	NM_032304.4	ENSP00000374353.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 20, 2024

The c.325G>C (p.G109R) alteration is located in exon 4 (coding exon 4) of the HAGHL gene. This alteration results from a G to C substitution at nucleotide position 325, causing the glycine (G) at amino acid position 109 to be replaced by an arginine (R). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	.;D;.;.;D;.;D;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.8	H;H;H;.;.;H;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;.;N;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.023	D;D;D;D;D;D;.;D;D
Sift4G	Benign	0.065	T;D;T;T;T;T;T;T;T
Polyphen		0.88	P;P;P;.;P;P;.;.;.
Vest4		0.69
MutPred		0.88		Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);Gain of methylation at G109 (P = 0.0391);.;
MVP		0.77
MPC		0.83
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.11
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1293840731; hg19: chr16-778352;