rs3213945

Positions:

• chr2-177538058-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003659.4(AGPS):​c.1856-16G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,246 control chromosomes in the GnomAD database, including 10,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (920 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9862 hom.)
• Consequence: AGPS NM_003659.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0780

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-177538058-G-T is Benign according to our data. Variant chr2-177538058-G-T is described in ClinVar as [Benign]. Clinvar id is 259117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-177538058-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGPS	NM_003659.4	c.1856-16G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000264167.11	NP_003650.1
AGPS	XM_011512041.3	c.1586-16G>T		splice_polypyrimidine_tract_variant, intron_variant			XP_011510343.1
AGPS	XM_047446104.1	c.1586-16G>T		splice_polypyrimidine_tract_variant, intron_variant			XP_047302060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPS	ENST00000264167.11	c.1856-16G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_003659.4	ENSP00000264167	A2

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13926 AN: 151972 Hom.: 917 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0931

Gnomad OTH AF: 0.0976

GnomAD3 exomes AF: 0.114 AC: 28563 AN: 251092 Hom.: 2378 AF XY: 0.117 AC XY: 15917 AN XY: 135720

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.0664

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.349

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.0922

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.103 AC: 149805 AN: 1460156 Hom.: 9862 Cov.: 32 AF XY: 0.104 AC XY: 75859 AN XY: 726430

Gnomad4 AFR exome AF: 0.0591

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.373

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.0795

Gnomad4 NFE exome AF: 0.0909

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.0915 AC: 13921 AN: 152090 Hom.: 920 Cov.: 32 AF XY: 0.0930 AC XY: 6915 AN XY: 74372

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0725

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0671

Gnomad4 NFE AF: 0.0931

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.0942 Hom.: 970

Bravo AF: 0.0909

Asia WGS AF: 0.231 AC: 800 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 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:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.5
DANN	Benign	0.74

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: rs3213945; hg19: chr2-178402786; COSMIC: COSV51562123;