Genetic Variant ENST00000397748.5:c.1613G>C (chr21-46136980-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000397748.5(FTCD):c.1613G>C(p.Arg538Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R538L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FTCD
ENST00000397748.5 missense

Scores

Splicing: ADA: 0.6908

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.46

Publications

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

FTCD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07695681).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397748.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FTCD	NM_206965.2	MANE Select	c.*7G>C		3_prime_UTR	Exon 14 of 14	NP_996848.1	O95954-1
FTCD	NM_001320412.2		c.1613G>C	p.Arg538Pro	missense	Exon 14 of 15	NP_001307341.1	O95954-2
FTCD	NM_006657.3		c.*2+5G>C		splice_region intron	N/A	NP_006648.1	O95954-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FTCD	ENST00000397748.5	TSL:1	c.1613G>C	p.Arg538Pro	missense	Exon 14 of 15	ENSP00000380856.1	O95954-2
FTCD	ENST00000397746.8	TSL:1 MANE Select	c.*7G>C		3_prime_UTR	Exon 14 of 14	ENSP00000380854.3	O95954-1
FTCD	ENST00000397743.1	TSL:1	c.*101G>C		3_prime_UTR	Exon 13 of 13	ENSP00000380851.1	B7WPK3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247346

AF XY:

0.00000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.47

CADD

Benign

2.8

(source)

DANN

Benign

0.44

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.29

M_CAP

Benign

0.011

MetaRNN

Benign

0.077

MetaSVM

Benign

-1.0

PhyloP100

-1.5

PROVEAN

Benign

-1.1

REVEL

Benign

0.14

Sift

Benign

0.038

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.16

MutPred

0.29

Loss of sheet (P = 0.0037)

MVP

0.18

ClinPred

0.025

GERP RS

-1.8

gMVP

0.62

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.69

dbscSNV1_RF

Benign

0.28

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.35

Position offset: 5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over