Genetic Variant NM_212482.4:c.278-46G>A (chr2-215433507-C-T) – ACMG Classification: Benign (-20 pts)

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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.140

Publications

7 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: 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

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=-0.83).

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FN1	NM_212482.4	MANE Select	c.278-46G>A	intron	N/A	NP_997647.2	P02751-15
FN1	NM_001306129.2		c.278-46G>A	intron	N/A	NP_001293058.2	P02751-7
FN1	NM_001365517.2		c.278-46G>A	intron	N/A	NP_001352446.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FN1	ENST00000354785.11	TSL:1 MANE Select	c.278-46G>A	intron	N/A	ENSP00000346839.4	P02751-15
FN1	ENST00000323926.10	TSL:1	c.278-46G>A	intron	N/A	ENSP00000323534.6	P02751-7
FN1	ENST00000336916.8	TSL:1	c.278-46G>A	intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33545

AN:

151938

Hom.:

4020

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.219

AC XY:

156189

AN XY:

712354

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

12042

24084

36126

48168

60210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9232

18464

27696

36928

46160

<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:

0.221

AC:

33561

AN:

152056

Hom.:

4020

Cov.:

AF XY:

0.216

AC XY:

16053

AN XY:

74326

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.247

AC:

16803

AN:

67974

Other (OTH)

AF:

0.201

AC:

423

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1292

2584

3877

5169

6461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

336

672

1008

1344

1680

<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:

0.222

Hom.:

758

Bravo

AF:

0.215

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.3

(source)

DANN

Benign

0.63

PhyloP100

0.14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over