NM_000138.5:c.6497-23G>C

Variant names:

• chr15-48434736-C-G
• rs3825962
• NM_000138.5:c.6497-23G>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.6497-23G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,612,150 control chromosomes in the GnomAD database, including 1,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.035 (289 hom., cov: 32)
  • Exomes 𝑓: 0.016 (1510 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0800
• Publications: 4 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-48434736-C-G is Benign according to our data. Variant chr15-48434736-C-G is described in ClinVar as Benign. ClinVar VariationId is 255304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 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.6497-23G>C		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.6497-23G>C		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.6497-23G>C		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.6497-23G>C		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.*2260-23G>C		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5317 AN: 152078 Hom.: 285 Cov.: 32

Gnomad AFR AF: 0.0623

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.0357

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0404 AC: 10146 AN: 250882 AF XY: 0.0355

Gnomad AFR exome AF: 0.0665

Gnomad AMR exome AF: 0.0808

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.00463

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0163 AC: 23796 AN: 1459954 Hom.: 1510 Cov.: 31 AF XY: 0.0159 AC XY: 11559 AN XY: 726312

African (AFR) AF: 0.0677 AC: 2260 AN: 33386

American (AMR) AF: 0.0785 AC: 3504 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 296 AN: 26102

East Asian (EAS) AF: 0.232 AC: 9189 AN: 39640

South Asian (SAS) AF: 0.0282 AC: 2434 AN: 86216

European-Finnish (FIN) AF: 0.00267 AC: 142 AN: 53256

Middle Eastern (MID) AF: 0.0135 AC: 76 AN: 5644

European-Non Finnish (NFE) AF: 0.00380 AC: 4226 AN: 1110794

Other (OTH) AF: 0.0277 AC: 1669 AN: 60266

GnomAD4 genome AF: 0.0350 AC: 5333 AN: 152196 Hom.: 289 Cov.: 32 AF XY: 0.0360 AC XY: 2682 AN XY: 74418

African (AFR) AF: 0.0623 AC: 2589 AN: 41534

American (AMR) AF: 0.0564 AC: 861 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.246 AC: 1270 AN: 5172

South Asian (SAS) AF: 0.0351 AC: 169 AN: 4820

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10590

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00398 AC: 271 AN: 68016

Other (OTH) AF: 0.0350 AC: 74 AN: 2114

Alfa AF: 0.0170 Hom.: 13

Bravo AF: 0.0412

Asia WGS AF: 0.135 AC: 467 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.83
CADD	Benign	1.1
DANN	Benign	0.62
PhyloP100		-0.080
BranchPoint Hunter		2.0
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: rs3825962; hg19: chr15-48726933; COSMIC: COSV57314444; COSMIC: COSV57314444;