rs137854486

Variant names:

• chr2-215376612-A-G
• rs137854486
• NM_212482.4:c.5773T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-215376612-A-G
• chr2-215376612-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_212482.4(FN1):​c.5773T>C​(p.Trp1925Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1925C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FN1 NM_212482.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• 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: 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 14 ACMG points.

• PS1: Transcript NM_212482.4 (FN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-215376610-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 192244.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 2-215376612-A-G is Pathogenic according to our data. Variant chr2-215376612-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3585436.Status of the report is criteria_provided_single_submitter, 1 stars.

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.5773T>C	p.Trp1925Arg	missense	Exon 36 of 46	NP_997647.2
	FN1	NM_001306129.2		c.5773T>C	p.Trp1925Arg	missense	Exon 36 of 47	NP_001293058.2
	FN1	NM_001365517.2		c.5503T>C	p.Trp1835Arg	missense	Exon 35 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.5773T>C	p.Trp1925Arg	missense	Exon 36 of 46	ENSP00000346839.4
	FN1	ENST00000323926.10	TSL:1	c.5773T>C	p.Trp1925Arg	missense	Exon 36 of 47	ENSP00000323534.6
	FN1	ENST00000336916.8	TSL:1	c.5500T>C	p.Trp1834Arg	missense	Exon 35 of 46	ENSP00000338200.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Spondylometaphyseal dysplasia - Sutcliffe type;C1866075:Glomerulopathy with fibronectin deposits 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.85		Gain of disorder (P = 0.0017)
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.93
Mutation Taster		=0/100	disease causing

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: rs137854486; hg19: chr2-216241335;