chr21-46145511-G-T

Variant names:

• chr21-46145511-G-T
• rs545214029
• NM_206965.2:c.1166C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_206965.2(FTCD):​c.1166C>A​(p.Thr389Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T389R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FTCD NM_206965.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06258553).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206965.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	NM_206965.2	MANE Select	c.1166C>A	p.Thr389Lys	missense	Exon 10 of 14	NP_996848.1
	FTCD	NM_001320412.2		c.1166C>A	p.Thr389Lys	missense	Exon 10 of 15	NP_001307341.1
	FTCD	NM_006657.3		c.1166C>A	p.Thr389Lys	missense	Exon 10 of 15	NP_006648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	ENST00000397746.8	TSL:1 MANE Select	c.1166C>A	p.Thr389Lys	missense	Exon 10 of 14	ENSP00000380854.3
	FTCD	ENST00000397748.5	TSL:1	c.1166C>A	p.Thr389Lys	missense	Exon 10 of 15	ENSP00000380856.1
	FTCD	ENST00000291670.9	TSL:1	c.1166C>A	p.Thr389Lys	missense	Exon 10 of 15	ENSP00000291670.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398664 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690226

African (AFR) AF: 0.00 AC: 0 AN: 31646

American (AMR) AF: 0.00 AC: 0 AN: 36228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 35810

South Asian (SAS) AF: 0.00 AC: 0 AN: 79368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079562

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74394

African (AFR) AF: 0.00 AC: 0 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.39
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PhyloP100		1.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.031
Sift	Benign	0.66	T
Sift4G	Benign	0.86	T
Polyphen		0.086	B
Vest4		0.20
MutPred		0.43		Gain of MoRF binding (P = 0.0452)
MVP		0.26
MPC		0.087
ClinPred		0.084	T
GERP RS		2.5
Varity_R		0.033
gMVP		0.18
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs545214029; hg19: chr21-47565425;