chr21-46136986-G-A

Position:

chr21-46136986-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001320412.2(FTCD):c.1607C>T(p.Thr536Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,612,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 2 hom. )

Consequence

FTCD
NM_001320412.2 missense

Scores

Splicing: ADA: 0.001207

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -5.46

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021563947).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_206965.2 linkuse as main transcript	c.*1C>T		3_prime_UTR_variant	14/14	ENST00000397746.8	NP_996848.1	O95954-1
FTCD	NM_001320412.2 linkuse as main transcript	c.1607C>T	p.Thr536Met	missense_variant	14/15		NP_001307341.1	O95954-2
FTCD	NM_006657.3 linkuse as main transcript	c.*1C>T		splice_region_variant	14/15		NP_006648.1	O95954-1
FTCD	NM_006657.3 linkuse as main transcript	c.*1C>T		3_prime_UTR_variant	14/15		NP_006648.1	O95954-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746 linkuse as main transcript	c.*1C>T		3_prime_UTR_variant	14/14	1	NM_206965.2	ENSP00000380854.3		O95954-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000808

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000359

AC:

AN:

247588

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

134496

show subpopulations

Gnomad AFR exome

AF:

0.000745

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000896

AC:

1309

AN:

1460790

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000571

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000447

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000719

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000371

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 02, 2022	This sequence variant is a single nucleotide substitution (C>T) at the first nucleotide of the 3' UTR of the FTCD gene. This variant has not been clinically annotated previously (ClinVar), and has not been observed in patients with FTCD-related disease in the literature, to our knowledge. This variant is present in control population datasets (gnomAD database 103 of 278956 alleles or 0.04%). Bioinformatic tools do not predict any effect of this variant on splicing, and this nucleotide is not well conserved across the species examined. Functiol studies testing the effect of this variant on protein expression have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this to be a variant of uncertain significance. ACMG Criteria: BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.19

DANN

Benign

0.97

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.41

M_CAP

Benign

0.016

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.34

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0090

Vest4

0.18

MVP

0.13

ClinPred

0.012

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.096

SpliceAI score (max)

0.16

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