21-46155458-C-T

Variant names:

• chr21-46155458-C-T
• rs2277820
• NM_206965.2:c.54+12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206965.2(FTCD):​c.54+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,607,302 control chromosomes in the GnomAD database, including 89,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8095 hom., cov: 34)
  • Exomes 𝑓: 0.32 (81846 hom.)
• Consequence: FTCD NM_206965.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.158
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-46155458-C-T is Benign according to our data. Variant chr21-46155458-C-T is described in ClinVar as Benign. ClinVar VariationId is 95427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2	c.54+12G>A		intron_variant	Intron 1 of 13	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.54+12G>A		intron_variant	Intron 1 of 14		NP_001307341.1
FTCD	NM_006657.3	c.54+12G>A		intron_variant	Intron 1 of 14		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.54+12G>A		intron_variant	Intron 1 of 13	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43503 AN: 152058 Hom.: 8085 Cov.: 34

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.289

GnomAD2 exomes AF: 0.383 AC: 95432 AN: 249248 AF XY: 0.378

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.823

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.315 AC: 458499 AN: 1455126 Hom.: 81846 Cov.: 31 AF XY: 0.318 AC XY: 229932 AN XY: 724190

African (AFR) AF: 0.107 AC: 3574 AN: 33410

American (AMR) AF: 0.589 AC: 26309 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6669 AN: 26082

East Asian (EAS) AF: 0.789 AC: 31280 AN: 39662

South Asian (SAS) AF: 0.447 AC: 38462 AN: 86098

European-Finnish (FIN) AF: 0.378 AC: 19779 AN: 52280

Middle Eastern (MID) AF: 0.274 AC: 1577 AN: 5760

European-Non Finnish (NFE) AF: 0.282 AC: 312010 AN: 1107026

Other (OTH) AF: 0.313 AC: 18839 AN: 60170

GnomAD4 genome AF: 0.286 AC: 43511 AN: 152176 Hom.: 8095 Cov.: 34 AF XY: 0.301 AC XY: 22411 AN XY: 74364

African (AFR) AF: 0.114 AC: 4752 AN: 41572

American (AMR) AF: 0.454 AC: 6948 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3472

East Asian (EAS) AF: 0.797 AC: 4105 AN: 5148

South Asian (SAS) AF: 0.462 AC: 2225 AN: 4812

European-Finnish (FIN) AF: 0.398 AC: 4214 AN: 10590

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19412 AN: 67982

Other (OTH) AF: 0.286 AC: 601 AN: 2104

Alfa AF: 0.288 Hom.: 12536

Bravo AF: 0.284

Asia WGS AF: 0.556 AC: 1931 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glutamate formiminotransferase deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.0
DANN	Benign	0.67
PhyloP100		-0.16
PromoterAI		-0.011	Neutral
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: rs2277820; hg19: chr21-47575372; COSMIC: COSV52428068; COSMIC: COSV52428068;