rs140605

Variant names:

• chr15-48497437-T-C
• rs140605
• NM_000138.5:c.2168-46A>G

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.2168-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,553,576 control chromosomes in the GnomAD database, including 60,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10638 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50161 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.10
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-48497437-T-C is Benign according to our data. Variant chr15-48497437-T-C is described in ClinVar as Benign. ClinVar VariationId is 255288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.2168-46A>G		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.2168-46A>G		intron	N/A	NP_001393645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.2168-46A>G		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.2168-46A>G		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.637-22787A>G		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52382 AN: 151850 Hom.: 10610 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.319

GnomAD2 exomes AF: 0.279 AC: 67458 AN: 242142 AF XY: 0.270

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.351

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.259 AC: 363291 AN: 1401608 Hom.: 50161 Cov.: 23 AF XY: 0.257 AC XY: 179881 AN XY: 700794

African (AFR) AF: 0.587 AC: 18854 AN: 32138

American (AMR) AF: 0.265 AC: 11772 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 5067 AN: 25728

East Asian (EAS) AF: 0.400 AC: 15577 AN: 38950

South Asian (SAS) AF: 0.215 AC: 18183 AN: 84648

European-Finnish (FIN) AF: 0.274 AC: 14380 AN: 52466

Middle Eastern (MID) AF: 0.282 AC: 1592 AN: 5654

European-Non Finnish (NFE) AF: 0.247 AC: 261954 AN: 1059362

Other (OTH) AF: 0.273 AC: 15912 AN: 58232

GnomAD4 genome AF: 0.345 AC: 52465 AN: 151968 Hom.: 10638 Cov.: 32 AF XY: 0.343 AC XY: 25481 AN XY: 74278

African (AFR) AF: 0.573 AC: 23709 AN: 41398

American (AMR) AF: 0.298 AC: 4550 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 618 AN: 3472

East Asian (EAS) AF: 0.357 AC: 1847 AN: 5176

South Asian (SAS) AF: 0.233 AC: 1121 AN: 4816

European-Finnish (FIN) AF: 0.264 AC: 2783 AN: 10550

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16715 AN: 67974

Other (OTH) AF: 0.319 AC: 674 AN: 2112

Alfa AF: 0.287 Hom.: 1587

Bravo AF: 0.359

Asia WGS AF: 0.317 AC: 1103 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.42
DANN	Benign	0.68
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140605; hg19: chr15-48789634;