rs10202709

Variant names:

• chr2-215433507-C-T
• rs10202709
• NM_212482.4:c.278-46G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_212482.4(FN1):​c.278-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,587,770 control chromosomes in the GnomAD database, including 44,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4020 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40152 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.140
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-215433507-C-T is Benign according to our data. Variant chr2-215433507-C-T is described in ClinVar as Benign. ClinVar VariationId is 1227596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.278-46G>A		intron_variant	Intron 2 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.278-46G>A		intron_variant	Intron 2 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33545 AN: 151938 Hom.: 4020 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.202

GnomAD2 exomes AF: 0.178 AC: 37656 AN: 211880 AF XY: 0.174

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.000521

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.226 AC: 324002 AN: 1435714 Hom.: 40152 Cov.: 30 AF XY: 0.219 AC XY: 156189 AN XY: 712354

African (AFR) AF: 0.248 AC: 8137 AN: 32750

American (AMR) AF: 0.111 AC: 4570 AN: 41054

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3469 AN: 25802

East Asian (EAS) AF: 0.000337 AC: 13 AN: 38610

South Asian (SAS) AF: 0.0469 AC: 3933 AN: 83874

European-Finnish (FIN) AF: 0.264 AC: 13811 AN: 52374

Middle Eastern (MID) AF: 0.161 AC: 907 AN: 5642

European-Non Finnish (NFE) AF: 0.253 AC: 277036 AN: 1096240

Other (OTH) AF: 0.204 AC: 12126 AN: 59368

GnomAD4 genome AF: 0.221 AC: 33561 AN: 152056 Hom.: 4020 Cov.: 32 AF XY: 0.216 AC XY: 16053 AN XY: 74326

African (AFR) AF: 0.243 AC: 10073 AN: 41454

American (AMR) AF: 0.152 AC: 2319 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 486 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.0444 AC: 214 AN: 4822

European-Finnish (FIN) AF: 0.268 AC: 2828 AN: 10558

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16803 AN: 67974

Other (OTH) AF: 0.201 AC: 423 AN: 2106

Alfa AF: 0.222 Hom.: 758

Bravo AF: 0.215

Asia WGS AF: 0.0400 AC: 140 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		0.14
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: rs10202709; hg19: chr2-216298230; COSMIC: COSV60566938; COSMIC: COSV60566938;