rs940739

Variant names:

• chr2-215391428-T-A
• rs940739
• NM_212482.4:c.4252+204A>T

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.4252+204A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,132 control chromosomes in the GnomAD database, including 9,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.32 (9238 hom., cov: 33)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.249
• Publications: 4 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=-0.89).
• BP6: Variant 2-215391428-T-A is Benign according to our data. Variant chr2-215391428-T-A is described in ClinVar as Benign. ClinVar VariationId is 1287570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.4252+204A>T		intron_variant	Intron 26 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.4252+204A>T		intron_variant	Intron 26 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48796 AN: 152014 Hom.: 9234 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.321 AC: 48819 AN: 152132 Hom.: 9238 Cov.: 33 AF XY: 0.322 AC XY: 23948 AN XY: 74352

African (AFR) AF: 0.123 AC: 5117 AN: 41518

American (AMR) AF: 0.350 AC: 5348 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3472

East Asian (EAS) AF: 0.159 AC: 827 AN: 5186

South Asian (SAS) AF: 0.513 AC: 2474 AN: 4826

European-Finnish (FIN) AF: 0.412 AC: 4349 AN: 10550

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28377 AN: 67966

Other (OTH) AF: 0.319 AC: 674 AN: 2114

Alfa AF: 0.364 Hom.: 1409

Bravo AF: 0.304

Asia WGS AF: 0.357 AC: 1238 AN: 3476

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	-0.89
CADD	Benign	0.57
DANN	Benign	0.51
PhyloP100		-0.25
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: rs940739; hg19: chr2-216256151;