rs35789560

Variant names:

• chr9-127813236-C-T
• rs35789560
• NM_004957.6:c.1396C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004957.6(FPGS):​c.1396C>T​(p.Arg466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00993 in 1,607,698 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (13 hom., cov: 32)
  • Exomes 𝑓: 0.010 (104 hom.)
• Consequence: FPGS NM_004957.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.67
• Publications: 20 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010068268).
• BP6: Variant 9-127813236-C-T is Benign according to our data. Variant chr9-127813236-C-T is described in ClinVar as Benign. ClinVar VariationId is 3341528.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004957.6. 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
	FPGS	NM_004957.6	MANE Select	c.1396C>T	p.Arg466Cys	missense	Exon 15 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.1318C>T	p.Arg440Cys	missense	Exon 14 of 14	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.1246C>T	p.Arg416Cys	missense	Exon 15 of 15	NP_001018088.1	Q05932-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPGS	ENST00000373247.7	TSL:1 MANE Select	c.1396C>T	p.Arg466Cys	missense	Exon 15 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.1384C>T		non_coding_transcript_exon	Exon 15 of 15
	FPGS	ENST00000910448.1		c.1498C>T	p.Arg500Cys	missense	Exon 16 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1273 AN: 152176 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00952 AC: 2329 AN: 244654 AF XY: 0.00950

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00250

Gnomad ASJ exome AF: 0.00375

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0322

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00969

GnomAD4 exome AF: 0.0101 AC: 14692 AN: 1455404 Hom.: 104 Cov.: 30 AF XY: 0.00987 AC XY: 7139 AN XY: 723478

African (AFR) AF: 0.00168 AC: 56 AN: 33406

American (AMR) AF: 0.00274 AC: 121 AN: 44184

Ashkenazi Jewish (ASJ) AF: 0.00331 AC: 85 AN: 25696

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.00335 AC: 286 AN: 85420

European-Finnish (FIN) AF: 0.0308 AC: 1616 AN: 52456

Middle Eastern (MID) AF: 0.00435 AC: 25 AN: 5744

European-Non Finnish (NFE) AF: 0.0109 AC: 12030 AN: 1108724

Other (OTH) AF: 0.00785 AC: 472 AN: 60140

GnomAD4 genome AF: 0.00836 AC: 1273 AN: 152294 Hom.: 13 Cov.: 32 AF XY: 0.00936 AC XY: 697 AN XY: 74470

African (AFR) AF: 0.00144 AC: 60 AN: 41554

American (AMR) AF: 0.00542 AC: 83 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4822

European-Finnish (FIN) AF: 0.0313 AC: 332 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 743 AN: 68022

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.0101 Hom.: 29

Bravo AF: 0.00672

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00977 AC: 1186

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.69
MVP		0.61
MPC		1.1
ClinPred		0.026	T
GERP RS		5.0
Varity_R		0.39
gMVP		0.73
Mutation Taster		=88/12	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: rs35789560; hg19: chr9-130575515; COSMIC: COSV99049243; COSMIC: COSV99049243;