rs137854488

Variant names:

• chr2-215406306-T-C
• rs137854488
• NM_212482.4:c.2918A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_212482.4(FN1):​c.2918A>G​(p.Tyr973Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FN1 NM_212482.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.02

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 2-215406306-T-C is Pathogenic according to our data. Variant chr2-215406306-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 16325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215406306-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.2918A>G	p.Tyr973Cys	missense_variant	Exon 19 of 46	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.2918A>G	p.Tyr973Cys	missense_variant	Exon 19 of 46	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glomerulopathy with fibronectin deposits 2 Pathogenic:3

Feb 19, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 10, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_212482.3(FN1):c.2918A>G, has been identified in exon 19 of 46 of the FN1 gene (NB: This variant is non-coding in alternative transcripts). The variant is predicted to result in a major amino acid change from tyrosine to cysteine at position 973 of the protein (NP_997647.1(FN1):p.(Tyr973Cys)). The tyrosine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Hep III heparin-binding domain (Castelletti, F., et al. (2008)) and fibronectin type III functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. The variant has been previously described as pathogenic and segregated with disease in multiple families with glomerulopathy with fibronectin deposits (ClinVar, Ohtsubo, H., et al. (2016), Ertoy Baydar, D., et al. (2013)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Aug 31, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016325 /PMID: 18268355). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27056061). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Spondylometaphyseal dysplasia - Sutcliffe type;C1866075:Glomerulopathy with fibronectin deposits 2 Pathogenic:1

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 973 of the FN1 protein (p.Tyr973Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with glomerulopathy with fibronectin deposits (PMID: 18268355, 32939031). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16325). 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. For these reasons, this variant has been classified as Pathogenic. -

FN1-related disorder Pathogenic:1

May 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FN1 c.2918A>G variant is predicted to result in the amino acid substitution p.Tyr973Cys. This variant has been reported in multiple individuals with glomerulopathy with fibronectin deposits and segregated with the disease in at least one family (see for example, Castelletti et al 2008. PubMed ID: 18268355; Jayasinghe et al 2020. PubMed ID: 32939031). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;.;.;.;D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;M;M;M;M;M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.;D;D;D
Vest4		0.98
MutPred		0.95		Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);Loss of ubiquitination at K976 (P = 0.0777);
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95

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: rs137854488; hg19: chr2-216271029;