rs200283734

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000460011.6(FTCD):n.-107C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,590,800 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 2 hom. )

Consequence

FTCD
ENST00000460011.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.02

Publications

2 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Laboratory for Molecular Medicine

FTCD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02941671).

BP6

Variant 21-46138593-G-A is Benign according to our data. Variant chr21-46138593-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209155.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000696 (106/152250) while in subpopulation NFE AF = 0.00116 (79/68002). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FTCD	NM_206965.2 link	c.1358C>T	p.Thr453Met	missense_variant	Exon 12 of 14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2 link	c.1358C>T	p.Thr453Met	missense_variant	Exon 12 of 15		NP_001307341.1
FTCD	NM_006657.3 link	c.1358C>T	p.Thr453Met	missense_variant	Exon 12 of 15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8 link	c.1358C>T	p.Thr453Met	missense_variant	Exon 12 of 14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000636

AC:

134

AN:

210802

AF XY:

0.000625

show subpopulations

Gnomad AFR exome

AF:

0.0000812

Gnomad AMR exome

AF:

0.000250

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.000484

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.000370

GnomAD4 exome

AF:

0.000715

AC:

1028

AN:

1438550

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

530

AN XY:

715322

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33320

American (AMR)

AF:

0.000163

AC:

AN:

42990

Ashkenazi Jewish (ASJ)

AF:

0.0000775

AC:

AN:

25814

East Asian (EAS)

AF:

0.000635

AC:

AN:

39342

South Asian (SAS)

AF:

0.0000472

AC:

AN:

84714

European-Finnish (FIN)

AF:

0.000202

AC:

AN:

39588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.000860

AC:

952

AN:

1107534

Other (OTH)

AF:

0.000468

AC:

AN:

59828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000696

AC:

106

AN:

152250

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.000691

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000710

AC:

ExAC

AF:

0.000592

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Uncertain:2

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 453 of the FTCD protein (p.Thr453Met). This variant is present in population databases (rs200283734, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FTCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 209155). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FTCD protein function with a negative predictive value of 80%. 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. -

not provided

Uncertain:1Benign:1

Dec 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in a large population cohort, zygosity and detailed clinical information was not reported (PMID: 30665703); This variant is associated with the following publications: (PMID: 30665703) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FTCD: BP4 -

Inborn genetic diseases

Uncertain:1

Feb 22, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1358C>T (p.T453M) alteration is located in exon 12 (coding exon 12) of the FTCD gene. This alteration results from a C to T substitution at nucleotide position 1358, causing the threonine (T) at amino acid position 453 to be replaced by a methionine (M). The p.T453M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L

PhyloP100

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.099

T;T;T

Polyphen

0.97

D;D;D

Vest4

0.19

MVP

0.53

MPC

0.20

ClinPred

0.95

GERP RS

-1.8

PromoterAI

-0.078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.17

Mutation Taster

=91/9

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over