chr21-46137050-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001320412.2(FTCD):​c.1543C>T​(p.Pro515Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FTCD NM_001320412.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0914768).
• BP6: Variant 21-46137050-G-A is Benign according to our data. Variant chr21-46137050-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2806923.Status of the report is criteria_provided_single_submitter, 1 stars.

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>T	p.Leu521Leu	synonymous	Exon 14 of 14	NP_996848.1	O95954-1
	FTCD	NM_001320412.2		c.1543C>T	p.Pro515Ser	missense	Exon 14 of 15	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.1563C>T	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>T	p.Pro515Ser	missense	Exon 14 of 15	ENSP00000380856.1	O95954-2
	FTCD	ENST00000397746.8	TSL:1 MANE Select	c.1563C>T	p.Leu521Leu	synonymous	Exon 14 of 14	ENSP00000380854.3	O95954-1
	FTCD	ENST00000291670.9	TSL:1	c.1563C>T	p.Leu521Leu	synonymous	Exon 14 of 15	ENSP00000291670.5	O95954-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461442 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glutamate formiminotransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.6
DANN	Benign	0.88
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.84
PROVEAN	Benign	1.2	N
REVEL	Benign	0.031
Sift	Benign	0.54	T
Sift4G	Benign	0.40	T
Polyphen		0.017	B
Vest4		0.25
MutPred		0.29		Loss of catalytic residue at P514 (P = 0.0121)
MVP		0.33
ClinPred		0.18	T
GERP RS		1.5
gMVP		0.12
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;