21-46137050-G-C

Variant names:

• chr21-46137050-G-C
• rs1601286855
• ENST00000397748.5:c.1543C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320412.2(FTCD):​c.1543C>G​(p.Pro515Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P515S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FTCD NM_001320412.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.836
• Publications: 0 publications found

Genes affected

FTCD (HGNC:3974): (formimidoyltransferase cyclodeaminase) The protein encoded by this gene is a bifunctional enzyme that channels 1-carbon units from formiminoglutamate, a metabolite of the histidine degradation pathway, to the folate pool. Mutations in this gene are associated with glutamate formiminotransferase deficiency. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Dec 2009]

FTCD Gene-Disease associations (from GenCC):

• formiminoglutamic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07760075).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320412.2. 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
	FTCD	NM_206965.2	MANE Select	c.1563C>G	p.Leu521Leu	synonymous	Exon 14 of 14	NP_996848.1	O95954-1
	FTCD	NM_001320412.2		c.1543C>G	p.Pro515Ala	missense	Exon 14 of 15	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.1563C>G	p.Leu521Leu	synonymous	Exon 14 of 15	NP_006648.1	O95954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	ENST00000397748.5	TSL:1	c.1543C>G	p.Pro515Ala	missense	Exon 14 of 15	ENSP00000380856.1	O95954-2
	FTCD	ENST00000397746.8	TSL:1 MANE Select	c.1563C>G	p.Leu521Leu	synonymous	Exon 14 of 14	ENSP00000380854.3	O95954-1
	FTCD	ENST00000291670.9	TSL:1	c.1563C>G	p.Leu521Leu	synonymous	Exon 14 of 15	ENSP00000291670.5	O95954-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.8
DANN	Benign	0.84
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.84
PROVEAN	Benign	1.4	N
REVEL	Benign	0.031
Sift	Benign	0.92	T
Sift4G	Benign	0.45	T
Polyphen		0.0070	B
Vest4		0.28
MutPred		0.35		Loss of catalytic residue at P514 (P = 0.0151)
MVP		0.32
ClinPred		0.27	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.097
Mutation Taster		=92/8	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: rs1601286855; hg19: chr21-47556964;