chr15-48492594-G-A

Variant names:

• chr15-48492594-G-A
• rs775257418
• NM_000138.5:c.2729-8C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000138.5(FBN1):​c.2729-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBN1 NM_000138.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005031
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-48492594-G-A is Benign according to our data. Variant chr15-48492594-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 527226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2729-8C>T		splice_region intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.2729-8C>T		splice_region 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.2729-8C>T		splice_region intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.2729-8C>T		splice_region intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.637-17944C>T		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.0000803 AC: 12 AN: 149462 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000811

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000629 AC: 143 AN: 227452 AF XY: 0.000525

Gnomad AFR exome AF: 0.000348

Gnomad AMR exome AF: 0.000227

Gnomad ASJ exome AF: 0.000756

Gnomad EAS exome AF: 0.000366

Gnomad FIN exome AF: 0.000672

Gnomad NFE exome AF: 0.000786

Gnomad OTH exome AF: 0.00129

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000149 AC: 210 AN: 1406438 Hom.: 0 Cov.: 26 AF XY: 0.000150 AC XY: 105 AN XY: 701926

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000509 AC: 16 AN: 31434

American (AMR) AF: 0.000693 AC: 29 AN: 41872

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 7 AN: 25342

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39062

South Asian (SAS) AF: 0.000219 AC: 18 AN: 82212

European-Finnish (FIN) AF: 0.000246 AC: 13 AN: 52816

Middle Eastern (MID) AF: 0.000718 AC: 4 AN: 5570

European-Non Finnish (NFE) AF: 0.0000944 AC: 101 AN: 1069920

Other (OTH) AF: 0.000344 AC: 20 AN: 58210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000803 AC: 12 AN: 149462 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 9 AN XY: 72766

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000492 AC: 2 AN: 40690

American (AMR) AF: 0.00 AC: 0 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.000811 AC: 8 AN: 9860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67264

Other (OTH) AF: 0.00 AC: 0 AN: 2038

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000194685), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00684 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Sep 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.38
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.016
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: rs775257418; hg19: chr15-48784791; COSMIC: COSV107345536;