chr2-177392835-G-GGCGCGA

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_003659.4(AGPS):c.49_54dupGCGAGC(p.Ala17_Ser18dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000064 in 1,548,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

AGPS
NM_003659.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.48

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000263 (4/151944) while in subpopulation SAS AF= 0.000414 (2/4830). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 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 rank	MANE	Protein	UniProt
AGPS	NM_003659.4 link	c.49_54dupGCGAGC	p.Ala17_Ser18dup	conservative_inframe_insertion	Exon 1 of 20	ENST00000264167.11	NP_003650.1	O00116
AGPS	XM_047446105.1 link	c.49_54dupGCGAGC	p.Ala17_Ser18dup	conservative_inframe_insertion	Exon 1 of 10		XP_047302061.1
AGPS	XM_011512041.3 link	c.-300_-299insGCGCGA		upstream_gene_variant			XP_011510343.1	B7Z3Q4
LOC100130691	NR_026966.1 link	n.-150_-145dupTCGCGC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGPS	ENST00000264167.11 link	c.49_54dupGCGAGC	p.Ala17_Ser18dup	conservative_inframe_insertion	Exon 1 of 20	1	NM_003659.4	ENSP00000264167.4		O00116

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

144012

Hom.:

AF XY:

0.000201

AC XY:

AN XY:

79754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.000242

GnomAD4 exome

AF:

0.0000680

AC:

AN:

1396086

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

690202

show subpopulations

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:

0.000932

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000120

Gnomad4 OTH exome

AF:

0.000138

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000416

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.49_54dup, results in the insertion of 2 amino acid(s) of the AGPS protein (p.Ala17_Ser18dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771730798, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AGPS-related conditions. 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

Uncertain:1

May 04, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGPS c.49_54dupGCGAGC (p.Ala17_Ser18dup) results in an in-frame duplication that is predicted to duplicate 2 amino acids into the encoded protein. The variant allele was found at a frequency of 0.00017 in 144012 control chromosomes, predominantly at a frequency of 0.00098 within the South Asian subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in AGPS causing Rhizomelic Chondrodysplasia Punctata (0.00098 vs 0.0011). To our knowledge, no occurrence of c.49_54dupGCGAGC in individuals affected with Rhizomelic Chondrodysplasia Punctata and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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