21-46136482-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000397748.5(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 ENST00000397748.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.414

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]

ACMG classification

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=3, 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 GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FTCD	NM_001320412.2	c.1691C>A	p.Thr564Lys	missense_variant	15/15
FTCD	NM_006657.3	c.*15C>A		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FTCD	ENST00000397748.5	c.1691C>A	p.Thr564Lys	missense_variant	15/15	1
FTCD	ENST00000291670.9	c.*15C>A		3_prime_UTR_variant	15/15	1		P1
FTCD	ENST00000460011.6	c.*85C>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 647 AN: 152118 Hom.: 3 Cov.: 30

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.: 2 AF XY: 0.000996 AC XY: 133 AN XY: 133472

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.: 6 Cov.: 31 AF XY: 0.000519 AC XY: 377 AN XY: 726472

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.: 3 Cov.: 30 AF XY: 0.00402 AC XY: 299 AN XY: 74444

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.: 1

Bravo AF: 0.00467

ESP6500AA AF: 0.0120 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00121 AC: 141

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

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, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		0.28	B
Vest4		0.19
MVP		0.31
ClinPred		0.0032	T
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

Other links and lift over

dbSNP: rs114980528; hg19: chr21-47556396;