rs1553659131

Positions:

• chr2-215428306-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000354785.11(FN1):​c.718T>G​(p.Tyr240Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y240C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FN1 ENST00000354785.11 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 7.07

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Fibronectin type-I 5 (size 44) in uniprot entity FINC_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000354785.11
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FN1. . Gene score misZ 1.646 (greater than the threshold 3.09). Trascript score misZ 3.6477 (greater than threshold 3.09). GenCC has associacion of gene with glomerulopathy with fibronectin deposits 2, fibronectin glomerulopathy, spondylometaphyseal dysplasia, 'corner fracture' type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 2-215428306-A-C is Pathogenic according to our data. Variant chr2-215428306-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424646.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-215428306-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FN1	NM_212482.4	c.718T>G	p.Tyr240Asp	missense_variant	6/46	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.718T>G	p.Tyr240Asp	missense_variant	6/46	1	NM_212482.4	ENSP00000346839	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondylometaphyseal dysplasia - Sutcliffe type Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Spondylometaphyseal dysplasia, corner fracture type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29100092). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29100092). -

Spondylometaphyseal dysplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CHU Sainte-Justine Research Center, University of Montreal

Feb 25, 2017

6 Individuals with novel FN1 mutations and spondylometaphyseal dysplasia -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;D;D;D;.
Vest4		0.60
MutPred		0.91		Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);Loss of MoRF binding (P = 0.0488);
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553659131; hg19: chr2-216293029;