21-46138498-GCC-GC

Variant names:

• chr21-46138498-GC-G
• rs372045405
• NM_206965.2:c.1443+9delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_206965.2(FTCD):​c.1443+9delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,578,950 control chromosomes in the GnomAD database, including 553 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0063 (516 hom.)
• Consequence: FTCD NM_206965.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• 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 Gene-Disease associations (from GenCC):

• formiminoglutamic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 21-46138498-GC-G is Benign according to our data. Variant chr21-46138498-GC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	NM_206965.2	MANE Select	c.1443+9delG		intron	N/A	NP_996848.1
	FTCD	NM_001320412.2		c.1443+9delG		intron	N/A	NP_001307341.1
	FTCD	NM_006657.3		c.1443+9delG		intron	N/A	NP_006648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	ENST00000397746.8	TSL:1 MANE Select	c.1443+9delG		intron	N/A	ENSP00000380854.3
	FTCD	ENST00000397748.5	TSL:1	c.1443+9delG		intron	N/A	ENSP00000380856.1
	FTCD	ENST00000291670.9	TSL:1	c.1443+9delG		intron	N/A	ENSP00000291670.5

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152100 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00676

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.0148 AC: 2810 AN: 189994 AF XY: 0.0192

Gnomad AFR exome AF: 0.00421

Gnomad AMR exome AF: 0.000398

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00628 AC: 8961 AN: 1426732 Hom.: 516 Cov.: 32 AF XY: 0.00893 AC XY: 6322 AN XY: 708012

African (AFR) AF: 0.00353 AC: 117 AN: 33172

American (AMR) AF: 0.000533 AC: 22 AN: 41268

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25526

East Asian (EAS) AF: 0.00250 AC: 97 AN: 38870

South Asian (SAS) AF: 0.0980 AC: 8093 AN: 82620

European-Finnish (FIN) AF: 0.0000250 AC: 1 AN: 40012

Middle Eastern (MID) AF: 0.00349 AC: 15 AN: 4300

European-Non Finnish (NFE) AF: 0.000102 AC: 112 AN: 1101682

Other (OTH) AF: 0.00848 AC: 503 AN: 59282

GnomAD4 genome AF: 0.00485 AC: 739 AN: 152218 Hom.: 37 Cov.: 33 AF XY: 0.00669 AC XY: 498 AN XY: 74404

African (AFR) AF: 0.00368 AC: 153 AN: 41540

American (AMR) AF: 0.00144 AC: 22 AN: 15294

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

East Asian (EAS) AF: 0.00659 AC: 34 AN: 5162

South Asian (SAS) AF: 0.105 AC: 504 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67996

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.000609 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutamate formiminotransferase deficiency Benign:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs372045405; hg19: chr21-47558412;