NM_000138.5:c.6855T>C

Variant names:

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.6855T>C(p.Asp2285Asp) 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 1,613,772 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 97 hom., cov: 32)

Exomes 𝑓: 0.022 ( 679 hom. )

Consequence

FBN1
NM_000138.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -1.96

Publications

12 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=-0.87).

BP6

Variant 15-48430687-A-G is Benign according to our data. Variant chr15-48430687-A-G is described in ClinVar as Benign. ClinVar VariationId is 42412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.96 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.075 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.6855T>C	p.Asp2285Asp	synonymous	Exon 56 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.6855T>C	p.Asp2285Asp	synonymous	Exon 55 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.6855T>C	p.Asp2285Asp	synonymous	Exon 56 of 66	ENSP00000325527.5	P35555
FBN1	ENST00000559133.6	TSL:1	n.6855T>C		non_coding_transcript_exon	Exon 56 of 67	ENSP00000453958.2	H0YND0
FBN1	ENST00000674301.2		n.*306T>C		non_coding_transcript_exon	Exon 57 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4378

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0402

Gnomad AMI

AF:

0.0976

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.0812

Gnomad SAS

AF:

0.0468

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0298

AC:

7500

AN:

251296

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:

0.0741

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0223

AC:

32550

AN:

1461514

Hom.:

679

Cov.:

AF XY:

0.0223

AC XY:

16239

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.0399

AC:

1336

AN:

33450

American (AMR)

AF:

0.0537

AC:

2403

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

417

AN:

26116

East Asian (EAS)

AF:

0.107

AC:

4236

AN:

39688

South Asian (SAS)

AF:

0.0357

AC:

3077

AN:

86256

European-Finnish (FIN)

AF:

0.0146

AC:

780

AN:

53406

Middle Eastern (MID)

AF:

0.0260

AC:

150

AN:

5766

European-Non Finnish (NFE)

AF:

0.0166

AC:

18427

AN:

1111758

Other (OTH)

AF:

0.0286

AC:

1724

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1651

3303

4954

6606

8257

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:

4391

AN:

152258

Hom.:

Cov.:

AF XY:

0.0298

AC XY:

2217

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0402

AC:

1671

AN:

41540

American (AMR)

AF:

0.0384

AC:

588

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3464

East Asian (EAS)

AF:

0.0814

AC:

421

AN:

5174

South Asian (SAS)

AF:

0.0473

AC:

228

AN:

4822

European-Finnish (FIN)

AF:

0.0171

AC:

181

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1102

AN:

68030

Other (OTH)

AF:

0.0284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

209

418

627

836

1045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0233

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 (6)

Familial thoracic aortic aneurysm and aortic dissection (3)

Marfan syndrome (2)

not provided (2)

Acromicric dysplasia (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

-0.87

CADD

Benign

0.024

(source)

DANN

Benign

0.38

PhyloP100

-2.0

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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