NM_003659.4:c.20C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_003659.4(AGPS):c.20C>T(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,515,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

AGPS
NM_003659.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.290

Variant links:

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 links:

ENSG00000213963 (HGNC:):

ENSG00000213963 links:

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]

NFE2L2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0064480305).

BP6

Variant 2-177392809-C-T is Benign according to our data. Variant chr2-177392809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383646.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000401 (61/152184) while in subpopulation AFR AF= 0.00135 (56/41548). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGPS	NM_003659.4 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 20	ENST00000264167.11	NP_003650.1	O00116
AGPS	XM_047446105.1 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 10		XP_047302061.1
AGPS	XM_011512041.3 link	c.-326C>T		upstream_gene_variant			XP_011510343.1	B7Z3Q4
LOC100130691	NR_026966.1 link	n.-118G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGPS	ENST00000264167.11 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 20	1	NM_003659.4	ENSP00000264167.4		O00116

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000975

AC:

AN:

123112

Hom.:

AF XY:

0.0000578

AC XY:

AN XY:

69178

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000572

AC:

AN:

1363622

Hom.:

Cov.:

AF XY:

0.0000460

AC XY:

AN XY:

673640

show subpopulations

Gnomad4 AFR exome

AF:

0.00195

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000274

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.000142

GnomAD4 genome

AF:

0.000401

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000412

ExAC

AF:

0.000113

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 7 of the AGPS protein (p.Ala7Val). This variant is present in population databases (rs539573652, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with AGPS-related conditions. ClinVar contains an entry for this variant (Variation ID: 383646). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not specified

Benign:1

Feb 12, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.0064

T;T

MetaSVM

Uncertain

0.084

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.19

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.53

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0

B;.

Vest4

0.26

MutPred

0.21

Gain of catalytic residue at A7 (P = 0.0366);Gain of catalytic residue at A7 (P = 0.0366);

MVP

0.64

MPC

0.88

ClinPred

0.072

GERP RS

3.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.077

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over