7-15365564-G-A

Variant names:

• chr7-15365564-G-A
• rs139309795
• NM_001004320.2:c.1213C>T

Variant summary

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

The NM_001004320.2(AGMO):​c.1213C>T​(p.Arg405*) 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 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
AGMO	NM_001004320.2	c.1213C>T	p.Arg405*	stop_gained	Exon 12 of 13	ENST00000342526.8	NP_001004320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGMO	ENST00000342526.8	c.1213C>T	p.Arg405*	stop_gained	Exon 12 of 13	1	NM_001004320.2	ENSP00000341662.3
AGMO	ENST00000407277.6	c.103C>T	p.Arg35*	stop_gained	Exon 2 of 3	3		ENSP00000385742.2
AGMO	ENST00000418075.1	c.139C>T	p.Arg47*	stop_gained	Exon 2 of 3	3		ENSP00000394412.1

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

Aug 01, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 08, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;