rs112366266

Variant names:

• chr15-48508673-G-A
• rs112366266
• NM_000138.5:c.1746C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48508673-G-A
• chr15-48508673-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000138.5(FBN1):​c.1746C>T​(p.Cys582Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00636 in 1,613,700 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (35 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 1.00
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-48508673-G-A is Benign according to our data. Variant chr15-48508673-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00422 (643/152274) while in subpopulation NFE AF = 0.00681 (463/68020). AF 95% confidence interval is 0.00629. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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: 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.1746C>T	p.Cys582Cys	synonymous	Exon 15 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.1746C>T	p.Cys582Cys	synonymous	Exon 14 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.1746C>T	p.Cys582Cys	synonymous	Exon 15 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.1746C>T		non_coding_transcript_exon	Exon 15 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.1746C>T		non_coding_transcript_exon	Exon 15 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 643 AN: 152156 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00342 AC: 858 AN: 251218 AF XY: 0.00314

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00552

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00658 AC: 9622 AN: 1461426 Hom.: 35 Cov.: 32 AF XY: 0.00629 AC XY: 4576 AN XY: 727008

African (AFR) AF: 0.000986 AC: 33 AN: 33460

American (AMR) AF: 0.00186 AC: 83 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00417 AC: 109 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86244

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00788 AC: 8757 AN: 1111652

Other (OTH) AF: 0.00752 AC: 454 AN: 60384

GnomAD4 genome AF: 0.00422 AC: 643 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74458

African (AFR) AF: 0.00166 AC: 69 AN: 41556

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00681 AC: 463 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00487 Hom.: 2

Bravo AF: 0.00403

EpiCase AF: 0.00627

EpiControl AF: 0.00664

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	4	Marfan syndrome (4)
-	-	2	Connective tissue disorder (2)
-	-	1	Acromicric dysplasia (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (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	-0.41
CADD	Benign	7.0
DANN	Benign	0.65
PhyloP100		1.0
Mutation Taster		=93/7	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: rs112366266; hg19: chr15-48800870;