16-728869-G-T

Variant names:

• chr16-728869-G-T
• rs755156372
• NM_032304.4:c.574G>T

Variant summary

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

The NM_032304.4(HAGHL):​c.574G>T​(p.Val192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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=0.2279819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAGHL	NM_032304.4	c.574G>T	p.Val192Leu	missense_variant	Exon 6 of 8	ENST00000389703.8	NP_115680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAGHL	ENST00000389703.8	c.574G>T	p.Val192Leu	missense_variant	Exon 6 of 8	1	NM_032304.4	ENSP00000374353.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000825 AC: 2 AN: 242414 Hom.: 0 AF XY: 0.00000756 AC XY: 1 AN XY: 132208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457156 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 724630

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.047	T;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.045	N;.;.;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.63	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.99	D;.;D;D
Vest4		0.39
MutPred		0.49		Loss of MoRF binding (P = 0.103);Loss of MoRF binding (P = 0.103);Loss of MoRF binding (P = 0.103);Loss of MoRF binding (P = 0.103);
MVP		0.51
MPC		0.25
ClinPred		0.43	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs755156372; hg19: chr16-778869;