rs137854488

chr2-215406306-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 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:3
• 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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FN1
• 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/exons	MANE	UniProt
FN1	NM_212482.4	c.2918A>G	p.Tyr973Cys	missense_variant	19/46	ENST00000354785.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FN1	ENST00000354785.11	c.2918A>G	p.Tyr973Cys	missense_variant	19/46	1	NM_212482.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glomerulopathy with fibronectin deposits 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 19, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 10, 2019	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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

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
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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A
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;