2-177392936-C-T

Variant names:

• chr2-177392936-C-T
• rs34442536
• NM_003659.4:c.147C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003659.4(AGPS):​c.147C>T​(p.Pro49Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,550,112 control chromosomes in the GnomAD database, including 179 homozygotes. 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. P49P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (169 hom.)
• Consequence: AGPS NM_003659.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.153
• 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]

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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-177392936-C-T is Benign according to our data. Variant chr2-177392936-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0099 (1508/152254) while in subpopulation NFE AF = 0.0154 (1046/68006). AF 95% confidence interval is 0.0146. There are 10 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.147C>T	p.Pro49Pro	synonymous	Exon 1 of 20	NP_003650.1	O00116
	LOC100130691	NR_026966.1		n.-245G>A		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.147C>T	p.Pro49Pro	synonymous	Exon 1 of 20	ENSP00000264167.4	O00116
	AGPS	ENST00000642466.2		c.147C>T	p.Pro49Pro	synonymous	Exon 1 of 21	ENSP00000494433.2	A0A2R8YEL0
	AGPS	ENST00000927419.1		c.147C>T	p.Pro49Pro	synonymous	Exon 1 of 20	ENSP00000597478.1

Frequencies

GnomAD3 genomes AF: 0.00991 AC: 1508 AN: 152136 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00974 AC: 1418 AN: 145596 AF XY: 0.00970

Gnomad AFR exome AF: 0.00226

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.000241

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.00827

GnomAD4 exome AF: 0.0135 AC: 18932 AN: 1397858 Hom.: 169 Cov.: 32 AF XY: 0.0132 AC XY: 9129 AN XY: 689502

African (AFR) AF: 0.00177 AC: 56 AN: 31582

American (AMR) AF: 0.00353 AC: 126 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25158

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35726

South Asian (SAS) AF: 0.00179 AC: 142 AN: 79232

European-Finnish (FIN) AF: 0.0287 AC: 1378 AN: 48064

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5694

European-Non Finnish (NFE) AF: 0.0155 AC: 16693 AN: 1078740

Other (OTH) AF: 0.00906 AC: 525 AN: 57968

GnomAD4 genome AF: 0.00990 AC: 1508 AN: 152254 Hom.: 10 Cov.: 32 AF XY: 0.00987 AC XY: 735 AN XY: 74434

African (AFR) AF: 0.00243 AC: 101 AN: 41570

American (AMR) AF: 0.00346 AC: 53 AN: 15304

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

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5140

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10620

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1046 AN: 68006

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0132 Hom.: 42

Bravo AF: 0.00779

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	3	Rhizomelic chondrodysplasia punctata type 3 (3)
-	-	1	Rhizomelic chondrodysplasia punctata (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		-0.15
PromoterAI		0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs34442536; hg19: chr2-178257664;