21-46155489-G-C

Variant names:

• chr21-46155489-G-C
• NM_206965.2:c.35C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_206965.2(FTCD):​c.35C>G​(p.Ser12Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,556 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. S12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.75

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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
FTCD	NM_206965.2	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 15		NP_001307341.1
FTCD	NM_006657.3	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.35C>G	p.Ser12Trp	missense_variant	Exon 1 of 14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460556 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.2	H;H;H;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.83
MutPred		0.89		Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);
MVP		0.97
MPC		0.42
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47575403;