rs1197476780

Variant names:

• chr21-46151734-G-A
• rs1197476780
• NM_206965.2:c.460C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_206965.2(FTCD):​c.460C>T​(p.Gln154*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FTCD NM_206965.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.995
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-46151734-G-A is Pathogenic according to our data. Variant chr21-46151734-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3587718.Status of the report is criteria_provided_single_submitter, 1 stars.

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.460C>T	p.Gln154*	stop_gained	Exon 5 of 14	NP_996848.1	O95954-1
	FTCD	NM_001320412.2		c.460C>T	p.Gln154*	stop_gained	Exon 5 of 15	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.460C>T	p.Gln154*	stop_gained	Exon 5 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.460C>T	p.Gln154*	stop_gained	Exon 5 of 14	ENSP00000380854.3	O95954-1
	FTCD	ENST00000397748.5	TSL:1	c.460C>T	p.Gln154*	stop_gained	Exon 5 of 15	ENSP00000380856.1	O95954-2
	FTCD	ENST00000291670.9	TSL:1	c.460C>T	p.Gln154*	stop_gained	Exon 5 of 15	ENSP00000291670.5	O95954-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248976 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460394 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726498

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

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
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		0.99
Vest4		0.59
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=2/198	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1197476780; hg19: chr21-47571648;