rs375990689

Variant names:

• chr21-46151923-C-T
• rs375990689
• NM_206965.2:c.425G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46151923-C-T
• chr21-46151923-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_206965.2(FTCD):​c.425G>A​(p.Arg142Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,571,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000052 (1 hom.)
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206965.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	NM_206965.2	MANE Select	c.425G>A	p.Arg142Gln	missense	Exon 4 of 14	NP_996848.1	O95954-1
	FTCD	NM_001320412.2		c.425G>A	p.Arg142Gln	missense	Exon 4 of 15	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.425G>A	p.Arg142Gln	missense	Exon 4 of 15	NP_006648.1	O95954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	ENST00000397746.8	TSL:1 MANE Select	c.425G>A	p.Arg142Gln	missense	Exon 4 of 14	ENSP00000380854.3	O95954-1
	FTCD	ENST00000397748.5	TSL:1	c.425G>A	p.Arg142Gln	missense	Exon 4 of 15	ENSP00000380856.1	O95954-2
	FTCD	ENST00000291670.9	TSL:1	c.425G>A	p.Arg142Gln	missense	Exon 4 of 15	ENSP00000291670.5	O95954-1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000134 AC: 24 AN: 178448 AF XY: 0.000175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000763

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000811

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.0000522 AC: 74 AN: 1418794 Hom.: 1 Cov.: 31 AF XY: 0.0000684 AC XY: 48 AN XY: 702098

African (AFR) AF: 0.00 AC: 0 AN: 32502

American (AMR) AF: 0.000130 AC: 5 AN: 38432

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25362

East Asian (EAS) AF: 0.0000806 AC: 3 AN: 37230

South Asian (SAS) AF: 0.000442 AC: 36 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: 0.0000238 AC: 26 AN: 1090728

Other (OTH) AF: 0.0000511 AC: 3 AN: 58720

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.0000805 AC XY: 6 AN XY: 74488

African (AFR) AF: 0.0000481 AC: 2 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000102 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glutamate formiminotransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.82		Loss of MoRF binding (P = 0.0556)
MVP		0.96
MPC		0.39
ClinPred		0.95	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.94
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs375990689; hg19: chr21-47571837; COSMIC: COSV105870676; COSMIC: COSV105870676;