2-177392794-C-A

Position:

• chr2-177392794-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_003659.4(AGPS):​c.5C>A​(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 1,344,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: AGPS NM_003659.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

AGPS (HGNC:327): (alkylglycerone phosphate synthase) This gene is a member of the FAD-binding oxidoreductase/transferase type 4 family. It encodes a protein that catalyzes the second step of ether lipid biosynthesis in which acyl-dihydroxyacetonephosphate (DHAP) is converted to alkyl-DHAP by the addition of a long chain alcohol and the removal of a long-chain acid anion. The protein is localized to the inner aspect of the peroxisomal membrane and requires FAD as a cofactor. Mutations in this gene have been associated with rhizomelic chondrodysplasia punctata, type 3 and Zellweger syndrome. [provided by RefSeq, Jul 2008]

AGPS (HGNC:):

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38760334).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000298 (4/1344056) while in subpopulation AMR AF= 0.000106 (3/28404). AF 95% confidence interval is 0.000028. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGPS	NM_003659.4	c.5C>A	p.Ala2Glu	missense_variant	1/20	ENST00000264167.11	NP_003650.1
AGPS	XM_047446105.1	c.5C>A	p.Ala2Glu	missense_variant	1/10		XP_047302061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPS	ENST00000264167.11	c.5C>A	p.Ala2Glu	missense_variant	1/20	1	NM_003659.4	ENSP00000264167.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000298 AC: 4 AN: 1344056 Hom.: 0 Cov.: 32 AF XY: 0.00000151 AC XY: 1 AN XY: 662682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.36e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces alanine with glutamic acid at codon 2 of the AGPS protein (p.Ala2Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with AGPS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.41	T;T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.25	N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0040	B;.
Vest4		0.45
MutPred		0.14		Gain of solvent accessibility (P = 0.0789);Gain of solvent accessibility (P = 0.0789);
MVP		0.90
MPC		1.0
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.48
gMVP		0.50

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: rs946047503; hg19: chr2-178257522;