chr16-728117-G-A

Variant names:

• chr16-728117-G-A
• rs748523464
• NM_032304.4:c.172G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_032304.4(HAGHL):​c.172G>A​(p.Asp58Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,476,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense, splice_region
• Scores: Splicing: ADA: 0.02483
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032304.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	NM_032304.4	MANE Select	c.172G>A	p.Asp58Asn	missense splice_region	Exon 3 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.172G>A	p.Asp58Asn	missense splice_region	Exon 4 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.172G>A	p.Asp58Asn	missense splice_region	Exon 4 of 7	NP_996995.1	Q6PII5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAGHL	ENST00000389703.8	TSL:1 MANE Select	c.172G>A	p.Asp58Asn	missense splice_region	Exon 3 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.277G>A		splice_region non_coding_transcript_exon	Exon 3 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.172G>A	p.Asp58Asn	missense splice_region	Exon 4 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151992 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000422 AC: 3 AN: 71028 AF XY: 0.0000250

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000408 AC: 54 AN: 1324780 Hom.: 0 Cov.: 34 AF XY: 0.0000353 AC XY: 23 AN XY: 651586

African (AFR) AF: 0.00 AC: 0 AN: 26144

American (AMR) AF: 0.0000410 AC: 1 AN: 24388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21716

East Asian (EAS) AF: 0.00 AC: 0 AN: 29658

South Asian (SAS) AF: 0.000217 AC: 15 AN: 69142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3832

European-Non Finnish (NFE) AF: 0.0000352 AC: 37 AN: 1051254

Other (OTH) AF: 0.0000183 AC: 1 AN: 54700

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151992 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74252

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67974

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000109 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		2.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.80	P
Vest4		0.77
MutPred		0.91		Loss of catalytic residue at D58 (P = 0.0116)
MVP		0.69
MPC		0.59
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		0.087	Neutral
Varity_R		0.70
gMVP		0.76
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.28
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

Other links and lift over

dbSNP: rs748523464; hg19: chr16-778117;