rs61729373

Positions:

• chr21-46151966-C-T
• chrNT_187626.1-11024-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_206965.2(FTCD):​c.382G>A​(p.Glu128Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,566,986 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 5.56

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-AS1 (HGNC:40243): (FTCD antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017312586).
• BP6: Variant 21-46151966-C-T is Benign according to our data. Variant chr21-46151966-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 340437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FTCD	NM_206965.2	c.382G>A	p.Glu128Lys	missense_variant	4/14	ENST00000397746.8
FTCD-AS1	NR_170989.1	n.146+207C>T		intron_variant, non_coding_transcript_variant
FTCD	NM_001320412.2	c.382G>A	p.Glu128Lys	missense_variant	4/15
FTCD	NM_006657.3	c.382G>A	p.Glu128Lys	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FTCD	ENST00000397746.8	c.382G>A	p.Glu128Lys	missense_variant	4/14	1	NM_206965.2	P1
FTCD-AS1	ENST00000446649.1	n.146+207C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152218 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00189 AC: 322 AN: 170660 Hom.: 0 AF XY: 0.00212 AC XY: 196 AN XY: 92504

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000226

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.000475

Gnomad SAS exome AF: 0.000624

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00259

GnomAD4 exome AF: 0.00222 AC: 3141 AN: 1414650 Hom.: 4 Cov.: 31 AF XY: 0.00219 AC XY: 1529 AN XY: 699604

Gnomad4 AFR exome AF: 0.000278

Gnomad4 AMR exome AF: 0.000369

Gnomad4 ASJ exome AF: 0.000947

Gnomad4 EAS exome AF: 0.000216

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00263

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152336 Hom.: 0 Cov.: 34 AF XY: 0.00140 AC XY: 104 AN XY: 74486

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00258 Hom.: 2

Bravo AF: 0.00147

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00248 AC: 21

ExAC AF: 0.00206 AC: 240

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

FTCD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

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). -

Glutamate formiminotransferase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.21	T;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.94	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.11	B;B;B;B
Vest4		0.58
MVP		0.82
MPC		0.071
ClinPred		0.033	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs61729373; hg19: chr21-47571880; COSMIC: COSV99385682;