chr2-215430725-G-C

Variant names:

• chr2-215430725-G-C
• rs1181638652
• NM_212482.4:c.675C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_212482.4(FN1):​c.675C>G​(p.Cys225Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. C225F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FN1 NM_212482.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0550
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics, ClinGen
• glomerulopathy with fibronectin deposits 2

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a disulfide_bond (size 12) in uniprot entity FINC_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_212482.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-215430726-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1067072.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 2-215430725-G-C is Pathogenic according to our data. Variant chr2-215430725-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.675C>G	p.Cys225Trp	missense_variant	Exon 5 of 46	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.675C>G	p.Cys225Trp	missense_variant	Exon 5 of 46	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylometaphyseal dysplasia - Sutcliffe type Pathogenic:2

Sep 30, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (http://www.uniprot.org/uniprot/P02751). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29100092). -

Spondylometaphyseal dysplasia Pathogenic:1

Feb 25, 2017

CHU Sainte-Justine Research Center, University of Montreal

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

6 Individuals with novel FN1 mutations and spondylometaphyseal dysplasia -

not provided Pathogenic:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the FN1 protein (p.Cys225Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spondylometaphyseal dysplasia corner fracture type (PMID: 29100092, 33605604). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 424645). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys225 amino acid residue in FN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;.;.;.;.;D;.;.;.;.;.
Eigen	Benign	0.012
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M;M
PhyloP100		0.055
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
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		0.84
MutPred		0.96		Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);Gain of MoRF binding (P = 0.0151);
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		-2.1
Varity_R		0.94
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1181638652; hg19: chr2-216295448;