rs754659947

Variant names:

• chr21-46151909-C-T
• rs754659947
• NM_206965.2:c.439G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_206965.2(FTCD):​c.439G>A​(p.Glu147Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,564,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.53

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-AS1 (HGNC:40243): (FTCD antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2	c.439G>A	p.Glu147Lys	missense_variant	Exon 4 of 14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.439G>A	p.Glu147Lys	missense_variant	Exon 4 of 15		NP_001307341.1
FTCD	NM_006657.3	c.439G>A	p.Glu147Lys	missense_variant	Exon 4 of 15		NP_006648.1
FTCD-AS1	NR_170989.1	n.146+150C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.439G>A	p.Glu147Lys	missense_variant	Exon 4 of 14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000890 AC: 15 AN: 168566 Hom.: 0 AF XY: 0.0000657 AC XY: 6 AN XY: 91376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000207

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000218

GnomAD4 exome AF: 0.000110 AC: 156 AN: 1412304 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 73 AN XY: 698336

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.0000267

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.000334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000684

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152212 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000942 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutamate formiminotransferase deficiency Uncertain:2

Oct 15, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0105 - Mechanism of disease for this gene is unknown. 0106 - This gene is known to be associated with autosomal recessive disease. 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 4). 0304 - Variant is present in gnomAD <0.01 for recessive indication (18 heterozygotes, 0 homozygotes). 0501 - Missense variant consistently predicted to be damaging by in-silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (FTCD_N domain; NCBI). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Jul 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 expected to disrupt FTCD protein function. ClinVar contains an entry for this variant (Variation ID: 459968). This variant has not been reported in the literature in individuals affected with FTCD-related conditions. This variant is present in population databases (rs754659947, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 147 of the FTCD protein (p.Glu147Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.0	M;M;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.88		Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);Gain of MoRF binding (P = 0.0071);
MVP		0.95
MPC		0.38
ClinPred		0.74	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs754659947; hg19: chr21-47571823;