NM_032304.4:c.190C>T

Variant names:

• chr16-728135-C-T
• rs1316226583
• NM_032304.4:c.190C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032304.4(HAGHL):​c.190C>T​(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,323,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P64A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.809
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027197957).

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.190C>T	p.Pro64Ser	missense	Exon 3 of 8	NP_115680.1	Q6PII5-2
	HAGHL	NM_001323636.2		c.190C>T	p.Pro64Ser	missense	Exon 4 of 8	NP_001310565.1
	HAGHL	NM_207112.2		c.190C>T	p.Pro64Ser	missense	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.190C>T	p.Pro64Ser	missense	Exon 3 of 8	ENSP00000374353.3	Q6PII5-2
	HAGHL	ENST00000389701.9	TSL:1	n.295C>T		non_coding_transcript_exon	Exon 3 of 7
	HAGHL	ENST00000341413.8	TSL:2	c.190C>T	p.Pro64Ser	missense	Exon 4 of 7	ENSP00000341952.4	Q6PII5-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1323626 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 651420

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26044

American (AMR) AF: 0.00 AC: 0 AN: 24040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21906

East Asian (EAS) AF: 0.00 AC: 0 AN: 29596

South Asian (SAS) AF: 0.00 AC: 0 AN: 69398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3830

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1051778

Other (OTH) AF: 0.00 AC: 0 AN: 54692

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.027	T
PhyloP100		0.81
PROVEAN	Benign	1.9	N
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Vest4		0.097
MVP		0.088
ClinPred		0.043	T
GERP RS		0.57
PromoterAI		-0.098	Neutral
Varity_R		0.041
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1316226583; hg19: chr16-778135;