rs398124234

Variant names:

• chr21-46145925-G-GC
• rs398124234
• NM_206965.2:c.990dupG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1 PP5_Very_Strong BS1_Supporting BS2

The NM_206965.2(FTCD):​c.990dupG​(p.Pro331AlafsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 1,504,188 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 29)
  • Exomes 𝑓: 0.0051 (20 hom.)
• Consequence: FTCD NM_206965.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 0.00200
• Publications: 13 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 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-46145925-G-GC is Pathogenic according to our data. Variant chr21-46145925-G-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (555/149212) while in subpopulation NFE AF = 0.00591 (396/67014). AF 95% confidence interval is 0.00543. There are 3 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 of 14	NP_996848.1	O95954-1
	FTCD	NM_001320412.2		c.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 of 15	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 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.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 of 14	ENSP00000380854.3	O95954-1
	FTCD	ENST00000397748.5	TSL:1	c.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 of 15	ENSP00000380856.1	O95954-2
	FTCD	ENST00000291670.9	TSL:1	c.990dupG	p.Pro331AlafsTer2	frameshift	Exon 9 of 15	ENSP00000291670.5	O95954-1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 555 AN: 149106 Hom.: 3 Cov.: 29

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.000869

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00245

GnomAD2 exomes AF: 0.00291 AC: 326 AN: 112050 AF XY: 0.00317

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000825

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00914

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00507 AC: 6866 AN: 1354976 Hom.: 20 Cov.: 31 AF XY: 0.00493 AC XY: 3291 AN XY: 668200

African (AFR) AF: 0.000715 AC: 20 AN: 27984

American (AMR) AF: 0.00147 AC: 49 AN: 33236

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 12 AN: 24104

East Asian (EAS) AF: 0.0000308 AC: 1 AN: 32496

South Asian (SAS) AF: 0.00225 AC: 172 AN: 76488

European-Finnish (FIN) AF: 0.0106 AC: 362 AN: 34018

Middle Eastern (MID) AF: 0.000705 AC: 3 AN: 4258

European-Non Finnish (NFE) AF: 0.00565 AC: 6028 AN: 1065982

Other (OTH) AF: 0.00388 AC: 219 AN: 56410

GnomAD4 genome AF: 0.00372 AC: 555 AN: 149212 Hom.: 3 Cov.: 29 AF XY: 0.00368 AC XY: 268 AN XY: 72842

African (AFR) AF: 0.00101 AC: 41 AN: 40542

American (AMR) AF: 0.00159 AC: 24 AN: 15124

Ashkenazi Jewish (ASJ) AF: 0.000869 AC: 3 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4842

South Asian (SAS) AF: 0.00150 AC: 7 AN: 4652

European-Finnish (FIN) AF: 0.00763 AC: 79 AN: 10358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00591 AC: 396 AN: 67014

Other (OTH) AF: 0.00242 AC: 5 AN: 2064

Alfa AF: 0.00335 Hom.: 0

Bravo AF: 0.00335

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Glutamate formiminotransferase deficiency (11)
6	1	-	not provided (7)
1	-	-	FTCD-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0020
Mutation Taster		=25/175	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs398124234; hg19: chr21-47565839; COSMIC: COSV52425520; COSMIC: COSV52425520;