16-728135-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032304.4(HAGHL):c.190C>G(p.Pro64Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,323,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: HAGHL NM_032304.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.809

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050058186).
• BP6: Variant 16-728135-C-G is Benign according to our data. Variant chr16-728135-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2610564.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAGHL	NM_032304.4	c.190C>G	p.Pro64Ala	missense_variant	3/8	ENST00000389703.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAGHL	ENST00000389703.8	c.190C>G	p.Pro64Ala	missense_variant	3/8	1	NM_032304.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1323628 Hom.: 0 Cov.: 34 AF XY: 0.00000768 AC XY: 5 AN XY: 651420

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: 0.0000720

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	9.1
Dann	Benign	0.91
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.050	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.91	N;N;N;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.030	N;N;N;N;N;N;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.60	T;T;T;T;T;T;.;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;.;.;.
Vest4		0.058
MutPred		0.49		Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);Gain of methylation at R68 (P = 0.0694);.;
MVP		0.26
MPC		0.19
ClinPred		0.018	T
GERP RS		0.57
Varity_R		0.033
gMVP		0.15

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: rs1316226583; hg19: chr16-778135;