rs560217758

Variant names:

• chr2-177393003-A-G
• rs560217758
• NM_003659.4:c.214A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-177393003-A-G
• chr2-177393003-A-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_003659.4(AGPS):​c.214A>G​(p.Thr72Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,550,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: AGPS NM_003659.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 B:2
• Conservation: PhyloP100: 0.226
• Publications: 4 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]

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: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008210868).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000328 (50/152274) while in subpopulation AMR AF = 0.00105 (16/15308). AF 95% confidence interval is 0.000655. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.214A>G	p.Thr72Ala	missense	Exon 1 of 20	NP_003650.1	O00116

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPS	ENST00000264167.11	TSL:1 MANE Select	c.214A>G	p.Thr72Ala	missense	Exon 1 of 20	ENSP00000264167.4	O00116
	AGPS	ENST00000642466.2		c.214A>G	p.Thr72Ala	missense	Exon 1 of 21	ENSP00000494433.2	A0A2R8YEL0
	AGPS	ENST00000927419.1		c.214A>G	p.Thr72Ala	missense	Exon 1 of 20	ENSP00000597478.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000321 AC: 47 AN: 146594 AF XY: 0.000329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000351

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000248 AC: 347 AN: 1397952 Hom.: 0 Cov.: 32 AF XY: 0.000264 AC XY: 182 AN XY: 689530

African (AFR) AF: 0.000190 AC: 6 AN: 31588

American (AMR) AF: 0.000644 AC: 23 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25158

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.000290 AC: 23 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48146

Middle Eastern (MID) AF: 0.0114 AC: 65 AN: 5696

European-Non Finnish (NFE) AF: 0.000178 AC: 192 AN: 1078756

Other (OTH) AF: 0.000655 AC: 38 AN: 57972

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74454

African (AFR) AF: 0.000168 AC: 7 AN: 41578

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67996

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.000184 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	3	-	Rhizomelic chondrodysplasia punctata type 3 (3)
-	1	-	AGPS-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.23
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.31
Sift	Benign	0.93	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.71
MPC		0.87
ClinPred		0.025	T
GERP RS		-0.59
PromoterAI		-0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.035
gMVP		0.32
Mutation Taster		=95/5	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: rs560217758; hg19: chr2-178257731; COSMIC: COSV51563526; COSMIC: COSV51563526;