rs1042078

Variant names:

• chr15-48410676-G-A
• rs1042078
• NM_000138.5:c.*314C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.*314C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 329,388 control chromosomes in the GnomAD database, including 78,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32375 hom., cov: 32)
  • Exomes 𝑓: 0.71 (45876 hom.)
• Consequence: FBN1 NM_000138.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.54
• Publications: 14 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-48410676-G-A is Benign according to our data. Variant chr15-48410676-G-A is described in ClinVar as Benign. ClinVar VariationId is 316354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.731 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.*314C>T		3_prime_UTR	Exon 66 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.*314C>T		3_prime_UTR	Exon 65 of 65	NP_001393645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.*314C>T		3_prime_UTR	Exon 66 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.*1738C>T		non_coding_transcript_exon	Exon 67 of 67	ENSP00000453958.2
	FBN1	ENST00000559133.6	TSL:1	n.*1738C>T		3_prime_UTR	Exon 67 of 67	ENSP00000453958.2

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97199 AN: 151910 Hom.: 32381 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.662

GnomAD4 exome AF: 0.714 AC: 126688 AN: 177360 Hom.: 45876 Cov.: 2 AF XY: 0.720 AC XY: 66914 AN XY: 92934

African (AFR) AF: 0.445 AC: 2117 AN: 4758

American (AMR) AF: 0.713 AC: 4485 AN: 6290

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 4318 AN: 5520

East Asian (EAS) AF: 0.535 AC: 5474 AN: 10226

South Asian (SAS) AF: 0.776 AC: 14442 AN: 18618

European-Finnish (FIN) AF: 0.708 AC: 6622 AN: 9348

Middle Eastern (MID) AF: 0.730 AC: 600 AN: 822

European-Non Finnish (NFE) AF: 0.730 AC: 81267 AN: 111348

Other (OTH) AF: 0.706 AC: 7363 AN: 10430

GnomAD4 genome AF: 0.639 AC: 97214 AN: 152028 Hom.: 32375 Cov.: 32 AF XY: 0.641 AC XY: 47628 AN XY: 74304

African (AFR) AF: 0.440 AC: 18216 AN: 41430

American (AMR) AF: 0.684 AC: 10450 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2767 AN: 3468

East Asian (EAS) AF: 0.557 AC: 2872 AN: 5154

South Asian (SAS) AF: 0.751 AC: 3621 AN: 4820

European-Finnish (FIN) AF: 0.716 AC: 7573 AN: 10570

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.729 AC: 49598 AN: 67990

Other (OTH) AF: 0.663 AC: 1400 AN: 2112

Alfa AF: 0.700 Hom.: 84093

Bravo AF: 0.628

Asia WGS AF: 0.636 AC: 2213 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Acromicric dysplasia (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	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.1
DANN	Benign	0.91
PhyloP100		2.5
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: rs1042078; hg19: chr15-48702873;