9-127813796-T-C

Variant names:

• chr9-127813796-T-C
• rs10106
• NM_004957.6:c.*192T>C

Variant summary

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

The NM_004957.6(FPGS):​c.*192T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,270,974 control chromosomes in the GnomAD database, including 116,866 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 0.45 (15675 hom., cov: 33)
  • Exomes 𝑓: 0.42 (101191 hom.)
• Consequence: FPGS NM_004957.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• Publications: 46 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

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.*192T>C		3_prime_UTR	Exon 15 of 15	NP_004948.4
	FPGS	NM_001288803.1		c.*192T>C		3_prime_UTR	Exon 14 of 14	NP_001275732.1	Q05932-4
	FPGS	NM_001018078.2		c.*192T>C		3_prime_UTR	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.*192T>C		3_prime_UTR	Exon 15 of 15	ENSP00000362344.2	Q05932-1
	FPGS	ENST00000460181.5	TSL:1	n.1944T>C		non_coding_transcript_exon	Exon 15 of 15
	FPGS	ENST00000910448.1		c.*192T>C		3_prime_UTR	Exon 16 of 16	ENSP00000580507.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68199 AN: 152032 Hom.: 15659 Cov.: 33

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.447

GnomAD4 exome AF: 0.421 AC: 471496 AN: 1118826 Hom.: 101191 Cov.: 33 AF XY: 0.420 AC XY: 223175 AN XY: 531204

African (AFR) AF: 0.522 AC: 12162 AN: 23320

American (AMR) AF: 0.459 AC: 4124 AN: 8994

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 5704 AN: 15452

East Asian (EAS) AF: 0.685 AC: 18305 AN: 26726

South Asian (SAS) AF: 0.368 AC: 10020 AN: 27192

European-Finnish (FIN) AF: 0.325 AC: 7591 AN: 23330

Middle Eastern (MID) AF: 0.364 AC: 1124 AN: 3084

European-Non Finnish (NFE) AF: 0.416 AC: 393083 AN: 945090

Other (OTH) AF: 0.425 AC: 19383 AN: 45638

GnomAD4 genome AF: 0.449 AC: 68266 AN: 152148 Hom.: 15675 Cov.: 33 AF XY: 0.443 AC XY: 32974 AN XY: 74374

African (AFR) AF: 0.519 AC: 21562 AN: 41512

American (AMR) AF: 0.456 AC: 6973 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1350 AN: 3468

East Asian (EAS) AF: 0.692 AC: 3577 AN: 5166

South Asian (SAS) AF: 0.381 AC: 1840 AN: 4826

European-Finnish (FIN) AF: 0.320 AC: 3391 AN: 10606

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28057 AN: 67976

Other (OTH) AF: 0.446 AC: 940 AN: 2108

Alfa AF: 0.429 Hom.: 29018

Bravo AF: 0.469

Asia WGS AF: 0.513 AC: 1786 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		-0.66
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs10106; hg19: chr9-130576075; COSMIC: COSV107437240; COSMIC: COSV107437240;