chr2-215361623-C-T

Variant names:

• chr2-215361623-C-T
• rs2106084754
• NM_212482.4:c.7366G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_212482.4(FN1):​c.7366G>A​(p.Val2456Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,457,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V2456V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FN1 NM_212482.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59
• Publications: 0 publications found

Genes affected

FN1 (HGNC:3778): (fibronectin 1) This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined. [provided by RefSeq, Jan 2016]

ATIC (HGNC:794): (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]

ATIC Gene-Disease associations (from GenCC):

• AICA-ribosiduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20164299).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212482.4. 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
	FN1	NM_212482.4	MANE Select	c.7366G>A	p.Val2456Ile	missense	Exon 46 of 46	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.7273G>A	p.Val2425Ile	missense	Exon 47 of 47	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.7096G>A	p.Val2366Ile	missense	Exon 45 of 45	NP_001352446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FN1	ENST00000354785.11	TSL:1 MANE Select	c.7366G>A	p.Val2456Ile	missense	Exon 46 of 46	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.7273G>A	p.Val2425Ile	missense	Exon 47 of 47	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.7000G>A	p.Val2334Ile	missense	Exon 46 of 46	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457498 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725438

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107998

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.71	N
PhyloP100		3.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.094
Sift	Benign	0.34	T
Sift4G	Benign	1.0	T
Polyphen		0.95	P
Vest4		0.38
MutPred		0.51		Gain of sheet (P = 0.0125)
MVP		0.63
MPC		0.29
ClinPred		0.34	T
GERP RS		6.0
Varity_R		0.038
gMVP		0.062
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs2106084754; hg19: chr2-216226346;