rs752005289

Variant names:

• chr2-215361645-GA-G
• rs752005289
• NM_212482.4:c.7363-20delT

Your query was ambiguous. Multiple possible variants found:

• chr2-215361645-GA-G
• chr2-215361645-GA-GAA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_212482.4(FN1):​c.7363-20delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,578,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0510
• 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-215361645-GA-G is Benign according to our data. Variant chr2-215361645-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1587702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 AD gene.

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.7363-20delT		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.7270-20delT		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.7093-20delT		intron	N/A	NP_001352446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FN1	ENST00000354785.11	TSL:1 MANE Select	c.7363-20delT		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.7270-20delT		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.6997-20delT		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149754 Hom.: 0 Cov.: 32

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: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.0000329 AC: 8 AN: 242898 AF XY: 0.0000380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000893

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000875 AC: 125 AN: 1428924 Hom.: 0 Cov.: 25 AF XY: 0.0000758 AC XY: 54 AN XY: 712436

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

African (AFR) AF: 0.0000306 AC: 1 AN: 32632

American (AMR) AF: 0.0000905 AC: 4 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5640

European-Non Finnish (NFE) AF: 0.000101 AC: 110 AN: 1083760

Other (OTH) AF: 0.0000845 AC: 5 AN: 59180

⚠️ 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 AF: 0.0000334 AC: 5 AN: 149754 Hom.: 0 Cov.: 32 AF XY: 0.0000274 AC XY: 2 AN XY: 72980

African (AFR) AF: 0.00 AC: 0 AN: 40700

American (AMR) AF: 0.00 AC: 0 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.000211 AC: 1 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67378

Other (OTH) AF: 0.000485 AC: 1 AN: 2062

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Spondylometaphyseal dysplasia - Sutcliffe type;C1866075:Glomerulopathy with fibronectin deposits 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.051

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: rs752005289; hg19: chr2-216226368; COSMIC: COSV60549709; COSMIC: COSV60549709;