2-177392936-C-T

Position:

• chr2-177392936-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003659.4(AGPS):​c.147C>T​(p.Pro49=) 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:10
• Conservation: PhyloP100: -0.153

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPS	NM_003659.4	c.147C>T	p.Pro49=	synonymous_variant	1/20	ENST00000264167.11
AGPS	XM_047446105.1	c.147C>T	p.Pro49=	synonymous_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPS	ENST00000264167.11	c.147C>T	p.Pro49=	synonymous_variant	1/20	1	NM_003659.4	A2

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

GnomAD3 exomes AF: 0.00974 AC: 1418 AN: 145596 Hom.: 23 AF XY: 0.00970 AC XY: 762 AN XY: 78546

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 SAS exome AF: 0.00146

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

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.00906

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

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000584

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0126 Hom.: 10

Bravo AF: 0.00779

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2016	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. -

Rhizomelic chondrodysplasia punctata type 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 12, 2017	- -

Rhizomelic chondrodysplasia punctata Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs34442536; hg19: chr2-178257664;