21-46137039-G-A

Position:

• chr21-46137039-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_206965.2(FTCD):​c.1574C>T​(p.Ala525Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_206965.2	c.1574C>T	p.Ala525Val	missense_variant	14/14	ENST00000397746.8	NP_996848.1
FTCD	NM_006657.3	c.1574C>T	p.Ala525Val	missense_variant	14/15		NP_006648.1
FTCD	NM_001320412.2	c.1554C>T	p.Ser518Ser	synonymous_variant	14/15		NP_001307341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.1574C>T	p.Ala525Val	missense_variant	14/14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glutamate formiminotransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 19, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FTCD protein function. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 525 of the FTCD protein (p.Ala525Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FTCD-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.62	T
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.022	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.59
MutPred		0.45		Loss of disorder (P = 0.0586);Loss of disorder (P = 0.0586);
MVP		0.62
MPC		0.30
ClinPred		0.93	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47556953;