chr2-215408298-CTGT-C

Variant names:

• chr2-215408298-CTGT-C
• rs1553636502
• NM_212482.4:c.2425_2427delACA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_212482.4(FN1):​c.2425_2427delACA​(p.Thr809del) variant causes a conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T809T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FN1 NM_212482.4 conservative_inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 9.76
• 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]

FN1 Gene-Disease associations (from GenCC):

• spondylometaphyseal dysplasia, 'corner fracture' type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• glomerulopathy with fibronectin deposits 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• fibronectin glomerulopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_212482.4. Strenght limited to Supporting due to length of the change: 1aa.

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.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 of 46	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 of 47	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 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.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 of 46	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 of 47	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.2425_2427delACA	p.Thr809del	conservative_inframe_deletion splice_region	Exon 16 of 46	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Spondylometaphyseal dysplasia (1)
-	1	-	Spondylometaphyseal dysplasia - Sutcliffe type (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs1553636502; hg19: chr2-216273021;