chr21-46137006-A-T

Position:

chr21-46137006-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

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 Conflicting classifications of pathogenicity (no stars).

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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

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:

FTCD (HGNC:):

FTCD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194395.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_206965.2 linkuse as main transcript	c.1607T>A	p.Leu536*	stop_gained	14/14	ENST00000397746.8	NP_996848.1	O95954-1
FTCD	NM_006657.3 linkuse as main transcript	c.1607T>A	p.Leu536*	stop_gained	14/15		NP_006648.1	O95954-1
FTCD	NM_001320412.2 linkuse as main transcript	c.1587T>A	p.Leu529Leu	synonymous_variant	14/15		NP_001307341.1	O95954-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8 linkuse as main transcript	c.1607T>A	p.Leu536*	stop_gained	14/14	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 04, 2020	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 30, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 30, 2021

Variant summary: FTCD c.1607T>A (p.Leu536X) results in a premature termination codon, which is predicted to remove the last five amino acids of the protein and keep the Cyclodeaminase domain intact (InterPro database). The variant allele was found at a frequency of 0.00029 in 247992 control chromosomes in the gnomAD database, including 1 homozygotes. c.1607T>A has been reported in the literature in multiple individuals affected with Glutamate Formiminotransferase Deficiency (Majumdar_2017, Ahrens-Nicklas_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both submitters classified the variant as pathogenic. However, at least one truncation variant upstream (c.1366dup/p.Glu456fs) has conflicting classification in ClinVar database. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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