7-15365564-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001004320.2(AGMO):c.1213C>T(p.Arg405Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: AGMO NM_001004320.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: -0.00100

Genes affected

AGMO (HGNC:33784): (alkylglycerol monooxygenase) The protein encoded by this gene is a tetrahydrobiopterin- and iron-dependent enzyme that cleaves the ether bond of alkylglycerols. Sequence comparisons distinguish this protein as forming a third, distinct class of tetrahydrobiopterin-dependent enzymes. Variations in this gene have been associated with decreased glucose-stimulated insulin response, type 2 diabetes, and susceptibility to intracranial aneurysms. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001004320.2 Downstream stopcodon found after 24 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGMO	NM_001004320.2	c.1213C>T	p.Arg405Ter	stop_gained	12/13	ENST00000342526.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGMO	ENST00000342526.8	c.1213C>T	p.Arg405Ter	stop_gained	12/13	1	NM_001004320.2	P1
AGMO	ENST00000407277.6	c.106C>T	p.Arg36Ter	stop_gained	2/3	3
AGMO	ENST00000418075.1	c.139C>T	p.Arg47Ter	stop_gained	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000646 AC: 98 AN: 151720 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000410 AC: 103 AN: 250928 Hom.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135618

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000186 AC: 271 AN: 1460780 Hom.: 0 Cov.: 30 AF XY: 0.000176 AC XY: 128 AN XY: 726680

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00556

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000645 AC: 98 AN: 151838 Hom.: 0 Cov.: 31 AF XY: 0.000647 AC XY: 48 AN XY: 74226

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000399 Hom.: 2

Bravo AF: 0.000763

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2023	Identified with the K234R variant on the same allele (in cis) in individuals with relapses in visceral leishmaniasis infection after treatment; the [K234R;R405X] allele was observed in both the heterozygous and homozygous state in the affected individuals and was also heterozygous in unaffected parents (Marquet et al., 2017); Published functional studies on the p.(R405*) variant alone demonstrate a damaging effect on protein expression and cellular activity; when combined with p.(K234R), functional studies demonstrate a more significant reduction in protein expression (Watschinger et al., 2018); Nonsense variant predicted to result in protein truncation as the last 41 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 28586473, 29741738, 31345219) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	35
Dann	Uncertain	0.97
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.021	N
MutationTaster	Benign	1.0	D
Vest4		0.74
ClinPred		0.17	T
GERP RS		-1.5

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: rs139309795; hg19: chr7-15405189; COSMIC: COSV61109477;