NM_206965.2:c.1607T>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PVS1_ModeratePM2PP5_Very_StrongBS1_Supporting

The NM_206965.2(FTCD):c.1607T>A(p.Leu536*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

FTCD
NM_206965.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.85

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0117 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-46137006-A-T is Pathogenic according to our data. Variant chr21-46137006-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0011 (168/152290) while in subpopulation AFR AF= 0.00392 (163/41556). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2 link	c.1607T>A	p.Leu536*	stop_gained	Exon 14 of 14	ENST00000397746.8	NP_996848.1	O95954-1
FTCD	NM_006657.3 link	c.1607T>A	p.Leu536*	stop_gained	Exon 14 of 15		NP_006648.1	O95954-1
FTCD	NM_001320412.2 link	c.1587T>A	p.Leu529Leu	synonymous_variant	Exon 14 of 15		NP_001307341.1	O95954-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8 link	c.1607T>A	p.Leu536*	stop_gained	Exon 14 of 14	1	NM_206965.2	ENSP00000380854.3		O95954-1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000290

AC:

AN:

247992

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

134636

show subpopulations

Gnomad AFR exome

AF:

0.00402

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000972

AC:

142

AN:

1461130

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.00367

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152290

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000839

Hom.:

Bravo

AF:

0.00121

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000404

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Pathogenic:4

Jul 04, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FTCD c.1607T>A (p.Leu536X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00029 in 247992 control chromosomes in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FTCD causing Glutamate Formiminotransferase Deficiency, allowing no conclusion about variant significance. c.1607T>A has been reported in the literature in multiple individuals affected with Glutamate Formiminotransferase Deficiency (examples: Majumdar_2017, Ahrens-Nicklas_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30740726, 31589614, 29178637). ClinVar contains an entry for this variant (Variation ID: 194395). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 28, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu536X variant in FTCD has been reported in 5 compound heterozygous and 1 homozygous individuals with formiminoglutamic aciduria (Majumdar 2017 PMID: 29178637, Ahrens-Nicklas 2019 PMID: 30740726). In 4 compound heterozygotes, the p.Leu536X variant was reported along with another disease-causing variant in FTCD, and these variants have been confirmed in trans in at least 1 individual. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 194395) and has been identified in 0.38% (286/75034) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is consistent with a recessive carrier frequency and the clinical manifestations of the disease. This nonsense variant leads to a premature termination codon at position 536. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing the last 6 amino acids of the coding region. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive formiminoglutamic aciduria. ACMG/AMP Criteria applied: PM3_Strong, PVS1_Moderate. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu536*) in the FTCD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the FTCD protein. This variant is present in population databases (rs149266909, gnomAD 0.4%). This premature translational stop signal has been observed in individuals with glutamate formiminotransferase deficiency (PMID: 29178637, 30740726). ClinVar contains an entry for this variant (Variation ID: 194395). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Apr 30, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.89

Vest4

0.59

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over