21-46136482-G-T

Position:

chr21-46136482-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001320412.2(FTCD):c.1691C>A(p.Thr564Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000938 in 1,612,630 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 30)

Exomes 𝑓: 0.00059 ( 6 hom. )

Consequence

FTCD
NM_001320412.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.414

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 links:

FTCD (HGNC:):

FTCD links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030518472).

BP6

Variant 21-46136482-G-T is Benign according to our data. Variant chr21-46136482-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00425 (647/152236) while in subpopulation AFR AF= 0.0138 (571/41524). AF 95% confidence interval is 0.0128. There are 3 homozygotes in gnomad4. There are 299 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_001320412.2 linkuse as main transcript	c.1691C>A	p.Thr564Lys	missense_variant	15/15		NP_001307341.1	O95954-2
FTCD	NM_006657.3 linkuse as main transcript	c.*15C>A		3_prime_UTR_variant	15/15		NP_006648.1	O95954-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
FTCD	ENST00000397748.5 linkuse as main transcript	c.1691C>A	p.Thr564Lys	missense_variant	15/15	1	ENSP00000380856.1	O95954-2
FTCD	ENST00000291670 linkuse as main transcript	c.*15C>A		3_prime_UTR_variant	15/15	1	ENSP00000291670.5	O95954-1
FTCD	ENST00000460011.6 linkuse as main transcript	n.*85C>A		non_coding_transcript_exon_variant	5/5	1	ENSP00000507070.1	Q49AR5

Frequencies

GnomAD3 genomes

AF:

0.00425

AC:

647

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00124

AC:

300

AN:

242800

Hom.:

AF XY:

0.000996

AC XY:

133

AN XY:

133472

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000350

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000592

AC:

865

AN:

1460394

Hom.:

Cov.:

AF XY:

0.000519

AC XY:

377

AN XY:

726472

show subpopulations

Gnomad4 AFR exome

AF:

0.0131

Gnomad4 AMR exome

AF:

0.00244

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000206

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152236

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

299

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.00347

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00467

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00121

AC:

141

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glutamate formiminotransferase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FTCD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Collagen 6-related myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.28

DANN

Benign

0.92

Eigen

Benign

-0.91

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.95

PROVEAN

Benign

-0.020

REVEL

Benign

0.063

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.28

Vest4

0.19

MVP

0.31

ClinPred

0.0032

GERP RS

0.48

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over