chr21-46145457-G-T

Position:

• chr21-46145457-G-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.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. 15/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0310

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 340422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46145457-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTCD	NM_206965.2	c.1220C>A	p.Thr407Lys	missense_variant	10/14	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.1220C>A	p.Thr407Lys	missense_variant	10/15		NP_001307341.1
FTCD	NM_006657.3	c.1220C>A	p.Thr407Lys	missense_variant	10/15		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.1220C>A	p.Thr407Lys	missense_variant	10/14	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152160 Hom.: 1 Cov.: 31

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

GnomAD3 exomes AF: 0.00200 AC: 337 AN: 168516 Hom.: 8 AF XY: 0.00190 AC XY: 172 AN XY: 90582

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 SAS exome AF: 0.000212

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.: 16 Cov.: 32 AF XY: 0.00135 AC XY: 943 AN XY: 696084

Gnomad4 AFR exome AF: 0.000187

Gnomad4 AMR exome AF: 0.000814

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.0000631

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152278 Hom.: 1 Cov.: 31 AF XY: 0.00112 AC XY: 83 AN XY: 74434

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00225 Hom.: 5

Bravo AF: 0.00120

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.00201 AC: 17

ExAC AF: 0.000924 AC: 106

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FTCD: BP4 -

Glutamate formiminotransferase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Benign	0.41
DEOGEN2	Benign	0.044	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.099	.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N;N;N;.
PrimateAI	Benign	0.35	T
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
Polyphen		0.050	B;B;B;B
Vest4		0.18
MVP		0.28
MPC		0.067
ClinPred		0.014	T
GERP RS		0.91
Varity_R		0.031
gMVP		0.15

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: rs148920158; hg19: chr21-47565371;