16-729365-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032304.4(HAGHL):c.758G>C(p.Arg253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,378,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 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. R253H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.217

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10240665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGHL	NM_032304.4	c.758G>C	p.Arg253Pro	missense_variant	8/8	ENST00000389703.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGHL	ENST00000389703.8	c.758G>C	p.Arg253Pro	missense_variant	8/8	1	NM_032304.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1378258 Hom.: 0 Cov.: 33 AF XY: 0.00000147 AC XY: 1 AN XY: 679382

Gnomad4 AFR exome AF: 0.00

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: 9.32e-7

Gnomad4 OTH exome AF: 0.0000175

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

Sep 27, 2021

The c.758G>C (p.R253P) alteration is located in exon 8 (coding exon 8) of the HAGHL gene. This alteration results from a G to C substitution at nucleotide position 758, causing the arginine (R) at amino acid position 253 to be replaced by a proline (P). 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
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	15
Dann	Benign	0.76
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	-0.057	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Benign	0.080	T
Sift4G	Benign	0.18	T
Polyphen		0.17	B
Vest4		0.17
MutPred		0.44		Gain of glycosylation at R253 (P = 0.0432);
MVP		0.46
MPC		0.35
ClinPred		0.078	T
GERP RS		-0.27
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-779365;