NM_000138.5:c.7819+8A>C

Variant names:

• chr15-48420679-T-G
• rs363838
• NM_000138.5:c.7819+8A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.7819+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,613,860 control chromosomes in the GnomAD database, including 638 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene FBN1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.025 (81 hom., cov: 32)
  • Exomes 𝑓: 0.016 (557 hom.)
• Consequence: FBN1 NM_000138.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.500
• Publications: 7 publications found

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

ACMG classification

Specifications for FBN1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 15-48420679-T-G is Benign according to our data. Variant chr15-48420679-T-G is described in ClinVar as Benign. ClinVar VariationId is 42433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.7819+8A>C		splice_region intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.7819+8A>C		splice_region intron	N/A	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.7819+8A>C		splice_region intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.*627+8A>C		splice_region intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.*1332+8A>C		splice_region intron	N/A	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3741 AN: 152114 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0226

GnomAD2 exomes AF: 0.0265 AC: 6652 AN: 250906 AF XY: 0.0250

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.0526

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0740

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00998

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0157 AC: 22894 AN: 1461628 Hom.: 557 Cov.: 32 AF XY: 0.0160 AC XY: 11631 AN XY: 727038

African (AFR) AF: 0.0389 AC: 1303 AN: 33476

American (AMR) AF: 0.0522 AC: 2334 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 309 AN: 26136

East Asian (EAS) AF: 0.107 AC: 4242 AN: 39694

South Asian (SAS) AF: 0.0354 AC: 3050 AN: 86256

European-Finnish (FIN) AF: 0.0118 AC: 627 AN: 53248

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5768

European-Non Finnish (NFE) AF: 0.00866 AC: 9628 AN: 1111936

Other (OTH) AF: 0.0208 AC: 1259 AN: 60390

GnomAD4 genome AF: 0.0247 AC: 3753 AN: 152232 Hom.: 81 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74434

African (AFR) AF: 0.0387 AC: 1609 AN: 41536

American (AMR) AF: 0.0352 AC: 539 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.0815 AC: 421 AN: 5168

South Asian (SAS) AF: 0.0471 AC: 227 AN: 4824

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 68028

Other (OTH) AF: 0.0223 AC: 47 AN: 2106

Alfa AF: 0.0162 Hom.: 59

Bravo AF: 0.0275

Asia WGS AF: 0.0710 AC: 248 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	1	Acromicric dysplasia (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.63
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs363838; hg19: chr15-48712876; COSMIC: COSV57318280; COSMIC: COSV57318280;