chr21-46151923-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_206965.2(FTCD):​c.425G>C​(p.Arg142Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FTCD
NM_206965.2 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.26

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-AS1 (HGNC:40243): (FTCD antisense RNA 1)

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FTCDNM_206965.2 linkc.425G>C p.Arg142Pro missense_variant Exon 4 of 14 ENST00000397746.8 NP_996848.1 O95954-1
FTCDNM_001320412.2 linkc.425G>C p.Arg142Pro missense_variant Exon 4 of 15 NP_001307341.1 O95954-2
FTCDNM_006657.3 linkc.425G>C p.Arg142Pro missense_variant Exon 4 of 15 NP_006648.1 O95954-1
FTCD-AS1NR_170989.1 linkn.146+164C>G intron_variant Intron 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FTCDENST00000397746.8 linkc.425G>C p.Arg142Pro missense_variant Exon 4 of 14 1 NM_206965.2 ENSP00000380854.3 O95954-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000141
AC:
2
AN:
1418794
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
702098
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32502
American (AMR)
AF:
0.00
AC:
0
AN:
38432
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25362
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37230
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81360
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48976
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5484
European-Non Finnish (NFE)
AF:
0.00000183
AC:
2
AN:
1090728
Other (OTH)
AF:
0.00
AC:
0
AN:
58720
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D;.;D;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.93
.;D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.2
H;H;H;.
PhyloP100
7.3
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.8
D;D;D;D
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.030
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.98
MutPred
0.79
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP
0.97
MPC
0.43
ClinPred
1.0
D
GERP RS
3.6
Varity_R
0.98
gMVP
0.98
Mutation Taster
=30/70
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs375990689; hg19: chr21-47571837; API