rs755836525

Variant names:

• chr2-177392795-G-A
• rs755836525
• NM_003659.4:c.6G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-177392795-G-A
• chr2-177392795-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS1

The NM_003659.4(AGPS):​c.6G>A​(p.Ala2Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000669 in 1,345,886 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: AGPS NM_003659.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.80
• Publications: 1 publications found

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]

ENSG00000213963 (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]

NFE2L2 Gene-Disease associations (from GenCC):

• immunodeficiency, developmental delay, and hypohomocysteinemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 2-177392795-G-A is Benign according to our data. Variant chr2-177392795-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1581501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000669 (9/1345886) while in subpopulation SAS AF = 0.0000863 (6/69504). AF 95% confidence interval is 0.000037. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003659.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPS	NM_003659.4	MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 20	NP_003650.1	O00116
	LOC100130691	NR_026966.1		n.-104C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPS	ENST00000264167.11	TSL:1 MANE Select	c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 20	ENSP00000264167.4	O00116
	AGPS	ENST00000642466.2		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 21	ENSP00000494433.2	A0A2R8YEL0
	AGPS	ENST00000927419.1		c.6G>A	p.Ala2Ala	synonymous	Exon 1 of 20	ENSP00000597478.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000465 AC: 5 AN: 107604 AF XY: 0.0000498

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000392

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000669 AC: 9 AN: 1345886 Hom.: 0 Cov.: 32 AF XY: 0.00000603 AC XY: 4 AN XY: 663728

African (AFR) AF: 0.00 AC: 0 AN: 27624

American (AMR) AF: 0.0000350 AC: 1 AN: 28600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20318

East Asian (EAS) AF: 0.00 AC: 0 AN: 34278

South Asian (SAS) AF: 0.0000863 AC: 6 AN: 69504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1068956

Other (OTH) AF: 0.00 AC: 0 AN: 55694

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	AGPS-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		3.8
PromoterAI		-0.46	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs755836525; hg19: chr2-178257523;