rs1250248

Variant names:

• chr2-215422370-A-G
• rs1250248
• NM_212482.4:c.1394-127T>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.1394-127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 948,840 control chromosomes in the GnomAD database, including 268,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.77 (45722 hom., cov: 33)
  • Exomes 𝑓: 0.74 (222401 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.322
• Publications: 38 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-215422370-A-G is Benign according to our data. Variant chr2-215422370-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286397.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.1394-127T>C		intron_variant	Intron 9 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.1394-127T>C		intron_variant	Intron 9 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117534 AN: 152008 Hom.: 45698 Cov.: 33

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.928

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.767

GnomAD4 exome AF: 0.744 AC: 592929 AN: 796712 Hom.: 222401 AF XY: 0.737 AC XY: 310114 AN XY: 420810

African (AFR) AF: 0.820 AC: 17067 AN: 20822

American (AMR) AF: 0.778 AC: 32327 AN: 41542

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 17475 AN: 21796

East Asian (EAS) AF: 0.938 AC: 34289 AN: 36552

South Asian (SAS) AF: 0.607 AC: 43387 AN: 71492

European-Finnish (FIN) AF: 0.806 AC: 37324 AN: 46310

Middle Eastern (MID) AF: 0.789 AC: 2817 AN: 3572

European-Non Finnish (NFE) AF: 0.734 AC: 378826 AN: 515892

Other (OTH) AF: 0.759 AC: 29417 AN: 38734

GnomAD4 genome AF: 0.773 AC: 117608 AN: 152128 Hom.: 45722 Cov.: 33 AF XY: 0.777 AC XY: 57766 AN XY: 74382

African (AFR) AF: 0.819 AC: 33995 AN: 41488

American (AMR) AF: 0.778 AC: 11884 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2758 AN: 3468

East Asian (EAS) AF: 0.927 AC: 4796 AN: 5174

South Asian (SAS) AF: 0.595 AC: 2870 AN: 4822

European-Finnish (FIN) AF: 0.824 AC: 8728 AN: 10594

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49987 AN: 67984

Other (OTH) AF: 0.769 AC: 1623 AN: 2110

Alfa AF: 0.739 Hom.: 21381

Bravo AF: 0.778

Asia WGS AF: 0.719 AC: 2504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.28
PhyloP100		-0.32
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: rs1250248; hg19: chr2-216287093;