16-727531-G-C

Variant names:

• chr16-727531-G-C
• NM_032304.4:c.22G>C

Variant summary

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

The NM_032304.4(HAGHL):​c.22G>C​(p.Val8Leu) 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 1,458,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAGHL	NM_032304.4	c.22G>C	p.Val8Leu	missense_variant	Exon 1 of 8	ENST00000389703.8	NP_115680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAGHL	ENST00000389703.8	c.22G>C	p.Val8Leu	missense_variant	Exon 1 of 8	1	NM_032304.4	ENSP00000374353.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458590 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725580

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22G>C (p.V8L) alteration is located in exon 1 (coding exon 1) of the HAGHL gene. This alteration results from a G to C substitution at nucleotide position 22, causing the valine (V) at amino acid position 8 to be replaced by a leucine (L). 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	0.69
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	.;T;.;.;.;T;T;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	.;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.3	L;L;.;L;.;.;.;L;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N;.;N;N;N;N;N;.;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.027	D;D;.;D;T;T;D;T;.;D
Sift4G	Benign	0.21	T;T;.;T;T;T;D;T;T;T
Polyphen		0.94	P;D;.;P;.;P;.;P;.;.
Vest4		0.42
MutPred		0.61		Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);Gain of catalytic residue at V8 (P = 0.0401);
MVP		0.77
MPC		0.60
ClinPred		0.88	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.56

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: chr16-777531;