rs4451422

Variant names:

• chr9-127814318-A-C
• rs4451422
• ENST00000467826.6:n.820A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-127814318-A-C
• chr9-127814318-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000467826.6(FPGS):​n.820A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 226,298 control chromosomes in the GnomAD database, including 20,447 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (13829 hom., cov: 32)
  • Exomes 𝑓: 0.41 (6618 hom.)
• Consequence: FPGS ENST00000467826.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• Publications: 30 publications found

Genes affected

FPGS (HGNC:3824): (folylpolyglutamate synthase) This gene encodes the folylpolyglutamate synthetase enzyme. This enzyme has a central role in establishing and maintaining both cytosolic and mitochondrial folylpolyglutamate concentrations and, therefore, is essential for folate homeostasis and the survival of proliferating cells. This enzyme catalyzes the ATP-dependent addition of glutamate moieties to folate and folate derivatives. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Jan 2014]

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPGS	NM_004957.6	c.*714A>C		downstream_gene_variant		ENST00000373247.7	NP_004948.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPGS	ENST00000373247.7	c.*714A>C		downstream_gene_variant		1	NM_004957.6	ENSP00000362344.2

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64218 AN: 151906 Hom.: 13815 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.432

GnomAD4 exome AF: 0.412 AC: 30601 AN: 74274 Hom.: 6618 Cov.: 4 AF XY: 0.411 AC XY: 14668 AN XY: 35674

African (AFR) AF: 0.395 AC: 546 AN: 1384

American (AMR) AF: 0.384 AC: 33 AN: 86

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 164 AN: 456

East Asian (EAS) AF: 0.729 AC: 204 AN: 280

South Asian (SAS) AF: 0.374 AC: 511 AN: 1366

European-Finnish (FIN) AF: 0.233 AC: 7 AN: 30

Middle Eastern (MID) AF: 0.274 AC: 45 AN: 164

European-Non Finnish (NFE) AF: 0.413 AC: 28113 AN: 68074

Other (OTH) AF: 0.402 AC: 978 AN: 2434

GnomAD4 genome AF: 0.423 AC: 64276 AN: 152024 Hom.: 13829 Cov.: 32 AF XY: 0.419 AC XY: 31112 AN XY: 74324

African (AFR) AF: 0.430 AC: 17820 AN: 41454

American (AMR) AF: 0.447 AC: 6831 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1348 AN: 3466

East Asian (EAS) AF: 0.692 AC: 3571 AN: 5158

South Asian (SAS) AF: 0.381 AC: 1835 AN: 4820

European-Finnish (FIN) AF: 0.315 AC: 3334 AN: 10580

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28048 AN: 67966

Other (OTH) AF: 0.431 AC: 910 AN: 2112

Alfa AF: 0.416 Hom.: 43637

Bravo AF: 0.439

Asia WGS AF: 0.510 AC: 1775 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.58
PhyloP100		-0.44

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4451422; hg19: chr9-130576597;