21-46145457-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206965.2(FTCD):c.1220C>A(p.Thr407Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,560,728 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 16 hom. )

Consequence

FTCD
NM_206965.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0310

Publications

5 publications found

Variant links:

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

FTCD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012105256).

BP6

Variant 21-46145457-G-T is Benign according to our data. Variant chr21-46145457-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340422.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 = 0.0011 (167/152278) while in subpopulation NFE AF = 0.000985 (67/68014). AF 95% confidence interval is 0.000795. There are 1 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FTCD	NM_206965.2 link	c.1220C>A	p.Thr407Lys	missense_variant	Exon 10 of 14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2 link	c.1220C>A	p.Thr407Lys	missense_variant	Exon 10 of 15		NP_001307341.1
FTCD	NM_006657.3 link	c.1220C>A	p.Thr407Lys	missense_variant	Exon 10 of 15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8 link	c.1220C>A	p.Thr407Lys	missense_variant	Exon 10 of 14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00200

AC:

337

AN:

168516

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000704

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.00351

GnomAD4 exome

AF:

0.00136

AC:

1910

AN:

1408450

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

943

AN XY:

696084

show subpopulations

African (AFR)

AF:

0.000187

AC:

AN:

32002

American (AMR)

AF:

0.000814

AC:

AN:

38082

Ashkenazi Jewish (ASJ)

AF:

0.0226

AC:

569

AN:

25218

East Asian (EAS)

AF:

0.00

AC:

AN:

36318

South Asian (SAS)

AF:

0.000175

AC:

AN:

79916

European-Finnish (FIN)

AF:

0.0000631

AC:

AN:

47526

Middle Eastern (MID)

AF:

0.00546

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00102

AC:

1102

AN:

1085346

Other (OTH)

AF:

0.00264

AC:

154

AN:

58360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

195

292

390

487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152278

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41560

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68014

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00201

AC:

ExAC

AF:

0.000924

AC:

106

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FTCD: BP4

Glutamate formiminotransferase deficiency

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.1

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.044

T;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.0

.;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.56

N;N;N;.

PhyloP100

-0.031

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.93

T;T;T;T

Sift4G

Benign

0.88

T;T;T;T

Vest4

0.18

ClinPred

0.014

GERP RS

0.91

Varity_R

0.031

gMVP

0.15

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over