Genetic Variant NM_206965.2:c.1122G>A (chr21-46145555-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_206965.2(FTCD):c.1122G>A(p.Val374Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,544,448 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

FTCD
NM_206965.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.144

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 21-46145555-C-T is Benign according to our data. Variant chr21-46145555-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 340425.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.144 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000546 (83/151884) while in subpopulation NFE AF = 0.00108 (73/67900). AF 95% confidence interval is 0.000877. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2 link	c.1122G>A	p.Val374Val	synonymous_variant	Exon 10 of 14	ENST00000397746.8	NP_996848.1	O95954-1
FTCD	NM_001320412.2 link	c.1122G>A	p.Val374Val	synonymous_variant	Exon 10 of 15		NP_001307341.1	O95954-2
FTCD	NM_006657.3 link	c.1122G>A	p.Val374Val	synonymous_variant	Exon 10 of 15		NP_006648.1	O95954-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8 link	c.1122G>A	p.Val374Val	synonymous_variant	Exon 10 of 14	1	NM_206965.2	ENSP00000380854.3		O95954-1

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000562

AC:

AN:

145846

AF XY:

0.000539

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.000947

GnomAD4 exome

AF:

0.00118

AC:

1645

AN:

1392564

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

790

AN XY:

686552

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31538

American (AMR)

AF:

0.000253

AC:

AN:

35590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25072

East Asian (EAS)

AF:

0.00

AC:

AN:

35628

South Asian (SAS)

AF:

0.0000885

AC:

AN:

79084

European-Finnish (FIN)

AF:

0.0000219

AC:

AN:

45708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00147

AC:

1584

AN:

1076544

Other (OTH)

AF:

0.000658

AC:

AN:

57752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

157

236

314

393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.000546

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41346

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00108

AC:

AN:

67900

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000590

Hom.:

Bravo

AF:

0.000518

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.3

(source)

DANN

Benign

0.79

PhyloP100

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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