chr21-46136261-G-A

Variant names:

• chr21-46136261-G-A
• rs77991819
• ENST00000856710.1:c.*298C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000494498.2(FTCD):​c.*236C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 591,536 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: FTCD ENST00000494498.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.271
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-46136261-G-A is Benign according to our data. Variant chr21-46136261-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 369369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0049 (746/152238) while in subpopulation AFR AF = 0.017 (705/41542). AF 95% confidence interval is 0.0159. There are 4 homozygotes in GnomAd4. There are 328 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000494498.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	NM_001320412.2		c.*193C>T		downstream_gene	N/A	NP_001307341.1	O95954-2
	FTCD	NM_006657.3		c.*236C>T		downstream_gene	N/A	NP_006648.1	O95954-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTCD	ENST00000856710.1		c.*298C>T		3_prime_UTR	Exon 15 of 15	ENSP00000526769.1
	FTCD	ENST00000494498.2	TSL:3	c.*236C>T		3_prime_UTR	Exon 6 of 6	ENSP00000507847.1	A0A804HKA5
	FTCD	ENST00000856709.1		c.*3-68C>T		intron	N/A	ENSP00000526768.1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152120 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000601 AC: 264 AN: 439298 Hom.: 2 Cov.: 4 AF XY: 0.000510 AC XY: 117 AN XY: 229250

African (AFR) AF: 0.0166 AC: 207 AN: 12452

American (AMR) AF: 0.000751 AC: 14 AN: 18638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13550

East Asian (EAS) AF: 0.00 AC: 0 AN: 30870

South Asian (SAS) AF: 0.0000243 AC: 1 AN: 41200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2550

European-Non Finnish (NFE) AF: 0.0000455 AC: 12 AN: 263832

Other (OTH) AF: 0.00117 AC: 30 AN: 25662

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152238 Hom.: 4 Cov.: 30 AF XY: 0.00441 AC XY: 328 AN XY: 74442

African (AFR) AF: 0.0170 AC: 705 AN: 41542

American (AMR) AF: 0.00163 AC: 25 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.00559

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.57
PhyloP100		-0.27

Splicing

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

Other links and lift over

dbSNP: rs77991819; hg19: chr21-47556175;