chr21-46145803-T-C

Variant names:

• chr21-46145803-T-C
• rs1060499859
• NM_206965.2:c.1098+15A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_206965.2(FTCD):​c.1098+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000081 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FTCD NM_206965.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.942
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-46145803-T-C is Benign according to our data. Variant chr21-46145803-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 402885.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTCD	NM_206965.2	c.1098+15A>G		intron_variant	Intron 9 of 13	ENST00000397746.8	NP_996848.1
FTCD	NM_001320412.2	c.1098+15A>G		intron_variant	Intron 9 of 14		NP_001307341.1
FTCD	NM_006657.3	c.1098+15A>G		intron_variant	Intron 9 of 14		NP_006648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTCD	ENST00000397746.8	c.1098+15A>G		intron_variant	Intron 9 of 13	1	NM_206965.2	ENSP00000380854.3

Frequencies

GnomAD3 genomes AF: 0.0000979 AC: 4 AN: 40842 Hom.: 0 Cov.: 0

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000222

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000811 AC: 16 AN: 197254 Hom.: 0 Cov.: 7 AF XY: 0.0000908 AC XY: 9 AN XY: 99110

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4610

American (AMR) AF: 0.00 AC: 0 AN: 2352

Ashkenazi Jewish (ASJ) AF: 0.000332 AC: 1 AN: 3010

East Asian (EAS) AF: 0.00 AC: 0 AN: 10750

South Asian (SAS) AF: 0.000199 AC: 3 AN: 15046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 642

European-Non Finnish (NFE) AF: 0.0000837 AC: 12 AN: 143300

Other (OTH) AF: 0.00 AC: 0 AN: 8738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000978 AC: 4 AN: 40894 Hom.: 0 Cov.: 0 AF XY: 0.000153 AC XY: 3 AN XY: 19634

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11240

American (AMR) AF: 0.00 AC: 0 AN: 4242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 942

East Asian (EAS) AF: 0.00 AC: 0 AN: 2068

South Asian (SAS) AF: 0.00 AC: 0 AN: 1236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 86

European-Non Finnish (NFE) AF: 0.000222 AC: 4 AN: 18056

Other (OTH) AF: 0.00 AC: 0 AN: 514

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000294109), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00641 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant not in splice consensus -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.73
DANN	Benign	0.30
PhyloP100		-0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060499859; hg19: chr21-47565717;