dbSNP rs11651: FN1:p.Tyr2387Tyr (chr2-215364969-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_212482.4(FN1):c.7161T>C(p.Tyr2387Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,573,182 control chromosomes in the GnomAD database, including 85,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6170 hom., cov: 31)

Exomes 𝑓: 0.33 ( 79067 hom. )

Consequence

FN1
NM_212482.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.46

Publications

25 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 links:

ATIC (HGNC:794): (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]

ATIC Gene-Disease associations (from GenCC):

AICA-ribosiduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ATIC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-215364969-A-G is Benign according to our data. Variant chr2-215364969-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.47 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	HGVSp	Effect	Exon Rank	Protein	UniProt
FN1	NM_212482.4	MANE Select	c.7161T>C	p.Tyr2387Tyr	synonymous	Exon 44 of 46	NP_997647.2	P02751-15
FN1	NM_001306129.2		c.7068T>C	p.Tyr2356Tyr	synonymous	Exon 45 of 47	NP_001293058.2	P02751-7
FN1	NM_001365517.2		c.6891T>C	p.Tyr2297Tyr	synonymous	Exon 43 of 45	NP_001352446.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FN1	ENST00000354785.11	TSL:1 MANE Select	c.7161T>C	p.Tyr2387Tyr	synonymous	Exon 44 of 46	ENSP00000346839.4	P02751-15
FN1	ENST00000323926.10	TSL:1	c.7068T>C	p.Tyr2356Tyr	synonymous	Exon 45 of 47	ENSP00000323534.6	P02751-7
FN1	ENST00000336916.8	TSL:1	c.6795T>C	p.Tyr2265Tyr	synonymous	Exon 44 of 46	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39727

AN:

151892

Hom.:

6160

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0943

Gnomad AMI

AF:

0.387

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.486

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.280

GnomAD2 exomes

AF:

0.322

AC:

63322

AN:

196418

AF XY:

0.335

show subpopulations

Gnomad AFR exome

AF:

0.0876

Gnomad AMR exome

AF:

0.327

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.320

Gnomad OTH exome

AF:

0.320

GnomAD4 exome

AF:

0.327

AC:

465312

AN:

1421172

Hom.:

79067

Cov.:

AF XY:

0.333

AC XY:

234233

AN XY:

703216

show subpopulations

African (AFR)

AF:

0.0797

AC:

2638

AN:

33096

American (AMR)

AF:

0.322

AC:

12665

AN:

39350

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

8894

AN:

25446

East Asian (EAS)

AF:

0.250

AC:

9664

AN:

38650

South Asian (SAS)

AF:

0.489

AC:

39646

AN:

81150

European-Finnish (FIN)

AF:

0.276

AC:

13717

AN:

49634

Middle Eastern (MID)

AF:

0.343

AC:

1964

AN:

5718

European-Non Finnish (NFE)

AF:

0.327

AC:

356600

AN:

1089212

Other (OTH)

AF:

0.331

AC:

19524

AN:

58916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

15352

30704

46056

61408

76760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11598

23196

34794

46392

57990

<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:

0.262

AC:

39757

AN:

152010

Hom.:

6170

Cov.:

AF XY:

0.262

AC XY:

19453

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0945

AC:

3921

AN:

41484

American (AMR)

AF:

0.303

AC:

4632

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

1219

AN:

3466

East Asian (EAS)

AF:

0.280

AC:

1444

AN:

5158

South Asian (SAS)

AF:

0.487

AC:

2332

AN:

4790

European-Finnish (FIN)

AF:

0.271

AC:

2865

AN:

10564

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.328

AC:

22300

AN:

67956

Other (OTH)

AF:

0.283

AC:

597

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1408

2816

4223

5631

7039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.309

Hom.:

12109

Bravo

AF:

0.255

Asia WGS

AF:

0.400

AC:

1391

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Glomerulopathy with fibronectin deposits 2 (1)

Spondylometaphyseal dysplasia - Sutcliffe type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.38

(source)

DANN

Benign

0.41

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=87/13

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