15-48428455-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000138.5(FBN1):c.6888G>A(p.Gln2296Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,614,014 control chromosomes in the GnomAD database, including 772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 94 hom., cov: 32)

Exomes 𝑓: 0.022 ( 678 hom. )

Consequence

FBN1
NM_000138.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: -0.00300

Publications

15 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 15-48428455-C-T is Benign according to our data. Variant chr15-48428455-C-T is described in ClinVar as Benign. ClinVar VariationId is 42413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.003 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0739 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.6888G>A	p.Gln2296Gln	synonymous	Exon 57 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.6888G>A	p.Gln2296Gln	synonymous	Exon 56 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.6888G>A	p.Gln2296Gln	synonymous	Exon 57 of 66	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6	TSL:1	n.6888G>A		non_coding_transcript_exon	Exon 57 of 67	ENSP00000453958.2	H0YND0
FBN1	ENST00000674301.2		n.*339G>A		non_coding_transcript_exon	Exon 58 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4374

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0401

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0801

Gnomad SAS

AF:

0.0470

Gnomad FIN

AF:

0.0172

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0298

AC:

7494

AN:

251298

AF XY:

0.0280

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.0540

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.0738

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0223

AC:

32547

AN:

1461766

Hom.:

678

Cov.:

AF XY:

0.0223

AC XY:

16239

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0399

AC:

1336

AN:

33474

American (AMR)

AF:

0.0537

AC:

2401

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

416

AN:

26128

East Asian (EAS)

AF:

0.107

AC:

4234

AN:

39690

South Asian (SAS)

AF:

0.0357

AC:

3078

AN:

86258

European-Finnish (FIN)

AF:

0.0146

AC:

779

AN:

53412

Middle Eastern (MID)

AF:

0.0262

AC:

151

AN:

5768

European-Non Finnish (NFE)

AF:

0.0166

AC:

18435

AN:

1111932

Other (OTH)

AF:

0.0284

AC:

1717

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1819

3638

5457

7276

9095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.0288

AC:

4386

AN:

152248

Hom.:

Cov.:

AF XY:

0.0298

AC XY:

2217

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0402

AC:

1669

AN:

41552

American (AMR)

AF:

0.0384

AC:

587

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3472

East Asian (EAS)

AF:

0.0803

AC:

414

AN:

5154

South Asian (SAS)

AF:

0.0475

AC:

229

AN:

4826

European-Finnish (FIN)

AF:

0.0172

AC:

183

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1103

AN:

68014

Other (OTH)

AF:

0.0284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

215

431

646

862

1077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0203

Hom.:

Bravo

AF:

0.0315

Asia WGS

AF:

0.0710

AC:

248

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0190

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Familial thoracic aortic aneurysm and aortic dissection (3)

not provided (3)

Marfan syndrome (2)

Acromicric dysplasia (1)

Ectopia lentis 1, isolated, autosomal dominant (1)

Geleophysic dysplasia (1)

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome (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

-0.31

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

-0.0030

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