rs25458

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000138.5(FBN1):c.1875T>C(p.Asn625Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,613,906 control chromosomes in the GnomAD database, including 29,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5984 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23995 hom. )

Consequence

FBN1
NM_000138.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:22

Conservation

PhyloP100: -0.0830

Publications

27 publications found

Variant links:

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

Marfan syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
familial thoracic aortic aneurysm and aortic dissection
Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Acromicric dysplasia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
progeroid and marfanoid aspect-lipodystrophy syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
stiff skin syndrome
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Weill-Marchesani syndrome 2, dominant
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
geleophysic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated ectopia lentis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neonatal Marfan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Weill-Marchesani syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ectopia lentis 1, isolated, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: G2P
Shprintzen-Goldberg syndrome
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

FBN1 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=-0.6).

BP6

Variant 15-48505110-A-G is Benign according to our data. Variant chr15-48505110-A-G is described in ClinVar as Benign. ClinVar VariationId is 42297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.083 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.1875T>C	p.Asn625Asn	synonymous	Exon 16 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.1875T>C	p.Asn625Asn	synonymous	Exon 15 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBN1	ENST00000316623.10	TSL:1 MANE Select	c.1875T>C	p.Asn625Asn	synonymous	Exon 16 of 66	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6	TSL:1	n.1875T>C		non_coding_transcript_exon	Exon 16 of 67	ENSP00000453958.2	H0YND0
FBN1	ENST00000674301.2		n.1875T>C		non_coding_transcript_exon	Exon 16 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes

AF:

0.246

AC:

37394

AN:

152016

Hom.:

5970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.199

Gnomad ASJ

AF:

0.0527

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.192

AC:

48399

AN:

251426

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.461

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.0580

Gnomad EAS exome

AF:

0.342

Gnomad FIN exome

AF:

0.206

Gnomad NFE exome

AF:

0.150

Gnomad OTH exome

AF:

0.167

GnomAD4 exome

AF:

0.166

AC:

243155

AN:

1461772

Hom.:

23995

Cov.:

AF XY:

0.164

AC XY:

119521

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.465

AC:

15547

AN:

33468

American (AMR)

AF:

0.202

AC:

9049

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0633

AC:

1655

AN:

26134

East Asian (EAS)

AF:

0.395

AC:

15690

AN:

39696

South Asian (SAS)

AF:

0.145

AC:

12493

AN:

86258

European-Finnish (FIN)

AF:

0.209

AC:

11168

AN:

53412

Middle Eastern (MID)

AF:

0.105

AC:

604

AN:

5768

European-Non Finnish (NFE)

AF:

0.150

AC:

166295

AN:

1111924

Other (OTH)

AF:

0.176

AC:

10654

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

11319

22639

33958

45278

56597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6238

12476

18714

24952

31190

<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:

0.246

AC:

37454

AN:

152134

Hom.:

5984

Cov.:

AF XY:

0.246

AC XY:

18327

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.449

AC:

18620

AN:

41462

American (AMR)

AF:

0.200

AC:

3052

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0527

AC:

183

AN:

3470

East Asian (EAS)

AF:

0.356

AC:

1844

AN:

5174

South Asian (SAS)

AF:

0.165

AC:

796

AN:

4822

European-Finnish (FIN)

AF:

0.205

AC:

2172

AN:

10592

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.148

AC:

10046

AN:

68010

Other (OTH)

AF:

0.210

AC:

443

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1319

2638

3957

5276

6595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.162

Hom.:

2231

Bravo

AF:

0.257

Asia WGS

AF:

0.266

AC:

924

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.131

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Familial thoracic aortic aneurysm and aortic dissection (3)

Marfan syndrome (2)

not provided (2)

Acromicric dysplasia (1)

Connective tissue disorder (1)

Ectopia lentis 1, isolated, autosomal dominant (1)

Geleophysic dysplasia (1)

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Stiff skin syndrome (1)

Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.6

(source)

DANN

Benign

0.50

PhyloP100

-0.083

Mutation Taster

=94/6

disease causing (ClinVar)

(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