16-728181-A-C

Variant names:

• chr16-728181-A-C
• rs1301518035
• NM_032304.4:c.236A>C

Variant summary

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

The NM_032304.4(HAGHL):​c.236A>C​(p.Asp79Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,307,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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: 1.40

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.236A>C	p.Asp79Ala	missense_variant	Exon 3 of 8	ENST00000389703.8	NP_115680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAGHL	ENST00000389703.8	c.236A>C	p.Asp79Ala	missense_variant	Exon 3 of 8	1	NM_032304.4	ENSP00000374353.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1307146 Hom.: 0 Cov.: 34 AF XY: 0.00000311 AC XY: 2 AN XY: 642684

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: 0.00000191

Gnomad4 OTH exome AF: 0.00

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

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236A>C (p.D79A) alteration is located in exon 3 (coding exon 3) of the HAGHL gene. This alteration results from a A to C substitution at nucleotide position 236, causing the aspartic acid (D) at amino acid position 79 to be replaced by an alanine (A). 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	0.84
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	.;D;.;.;D;.;D;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.81	.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.34	N;N;N;.;.;N;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;.;D;D
REVEL	Uncertain	0.44
Sift	Benign	0.053	T;T;T;D;T;D;.;T;D
Sift4G	Benign	0.12	T;T;T;T;D;T;T;T;D
Polyphen		1.0	D;D;D;.;D;P;.;.;.
Vest4		0.41
MutPred		0.57		Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);Gain of MoRF binding (P = 0.0262);.;
MVP		0.58
MPC		0.69
ClinPred		0.88	D
GERP RS		3.7
Varity_R		0.37
gMVP		0.51

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: rs1301518035; hg19: chr16-778181;