2-215420652-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_212482.4(FN1):c.1675+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,613,784 control chromosomes in the GnomAD database, including 3,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 248 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3249 hom. )

Consequence

FN1
NM_212482.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.242

Publications

9 publications found

Variant links:

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

FN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-215420652-T-C is Benign according to our data. Variant chr2-215420652-T-C is described in ClinVar as Benign. ClinVar VariationId is 1285279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4 link	c.1675+21A>G		intron_variant	Intron 11 of 45	ENST00000354785.11	NP_997647.2	P02751-15Q6MZM7Q9UQS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11 link	c.1675+21A>G		intron_variant	Intron 11 of 45	1	NM_212482.4	ENSP00000346839.4		P02751-15

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

6913

AN:

152128

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0543

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.130

Gnomad FIN

AF:

0.0261

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0591

Gnomad OTH

AF:

0.0617

GnomAD2 exomes

AF:

0.0594

AC:

14927

AN:

251390

AF XY:

0.0665

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.0349

Gnomad ASJ exome

AF:

0.0988

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0629

Gnomad OTH exome

AF:

0.0632

GnomAD4 exome

AF:

0.0612

AC:

89480

AN:

1461538

Hom.:

3249

Cov.:

AF XY:

0.0642

AC XY:

46672

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.0134

AC:

449

AN:

33476

American (AMR)

AF:

0.0358

AC:

1601

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0946

AC:

2471

AN:

26126

East Asian (EAS)

AF:

0.000378

AC:

AN:

39698

South Asian (SAS)

AF:

0.137

AC:

11809

AN:

86254

European-Finnish (FIN)

AF:

0.0302

AC:

1613

AN:

53408

Middle Eastern (MID)

AF:

0.109

AC:

631

AN:

5766

European-Non Finnish (NFE)

AF:

0.0603

AC:

67058

AN:

1111718

Other (OTH)

AF:

0.0635

AC:

3833

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

4202

8404

12605

16807

21009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2502

5004

7506

10008

12510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0454

AC:

6915

AN:

152246

Hom.:

248

Cov.:

AF XY:

0.0453

AC XY:

3376

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0156

AC:

649

AN:

41550

American (AMR)

AF:

0.0542

AC:

828

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.131

AC:

631

AN:

4814

European-Finnish (FIN)

AF:

0.0261

AC:

277

AN:

10622

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0591

AC:

4022

AN:

68016

Other (OTH)

AF:

0.0605

AC:

128

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

340

679

1019

1358

1698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0572

Hom.:

551

Bravo

AF:

0.0431

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 12, 2020

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

- -

Glomerulopathy with fibronectin deposits 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spondylometaphyseal dysplasia - Sutcliffe type

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

-0.81

CADD

Benign

0.94

(source)

DANN

Benign

0.59

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over