rs2304573

Variant names:

• chr2-215378927-A-G
• rs2304573
• NM_212482.4:c.5622+203T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_212482.4(FN1):​c.5622+203T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,160 control chromosomes in the GnomAD database, including 6,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6763 hom., cov: 33)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.400
• Publications: 7 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• glomerulopathy with fibronectin deposits 2

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-215378927-A-G is Benign according to our data. Variant chr2-215378927-A-G is described in ClinVar as Benign. ClinVar VariationId is 1239974.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

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.5622+203T>C		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.5622+203T>C		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.5352+203T>C		intron	N/A	NP_001352446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FN1	ENST00000354785.11	TSL:1 MANE Select	c.5622+203T>C		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.5622+203T>C		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.5349+203T>C		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42279 AN: 152042 Hom.: 6763 Cov.: 33

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.278 AC: 42304 AN: 152160 Hom.: 6763 Cov.: 33 AF XY: 0.285 AC XY: 21194 AN XY: 74392

African (AFR) AF: 0.246 AC: 10233 AN: 41518

American (AMR) AF: 0.381 AC: 5820 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1254 AN: 3470

East Asian (EAS) AF: 0.793 AC: 4101 AN: 5174

South Asian (SAS) AF: 0.273 AC: 1315 AN: 4820

European-Finnish (FIN) AF: 0.246 AC: 2602 AN: 10584

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16029 AN: 68002

Other (OTH) AF: 0.295 AC: 622 AN: 2110

Alfa AF: 0.261 Hom.: 22278

Bravo AF: 0.291

Asia WGS AF: 0.499 AC: 1737 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.2
DANN	Benign	0.67
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs2304573; hg19: chr2-216243650;