ENST00000316623:c.*2524A>G

Variant names:

• chr15-48408466-T-C
• rs75372203
• NM_000138.5:c.*2524A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000316623.10(FBN1):​c.*2524A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 152,764 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 33)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: FBN1 ENST00000316623.10 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.64
• Publications: 0 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-48408466-T-C is Benign according to our data. Variant chr15-48408466-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 316302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00295 (450/152332) while in subpopulation EAS AF = 0.0312 (162/5186). AF 95% confidence interval is 0.0273. There are 5 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000316623.10. 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.*2524A>G		3_prime_UTR	Exon 66 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.*2524A>G		3_prime_UTR	Exon 65 of 65	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.*2524A>G		3_prime_UTR	Exon 66 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000682170.1		n.*38A>G		downstream_gene	N/A
	FBN1	ENST00000682767.1		n.*38A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 442 AN: 152214 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0312

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00895

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.0139 AC: 6 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0154 AC XY: 4 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0141 AC: 6 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00295 AC: 450 AN: 152332 Hom.: 5 Cov.: 33 AF XY: 0.00348 AC XY: 259 AN XY: 74498

African (AFR) AF: 0.000192 AC: 8 AN: 41582

American (AMR) AF: 0.00960 AC: 147 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0312 AC: 162 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00895 AC: 95 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00272

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	not provided (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	-0.43
CADD	Benign	17
DANN	Benign	0.83
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism

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: rs75372203; hg19: chr15-48700663;