NM_000138.5:c.1960+76G>A

Variant names:

• chr15-48504949-C-T
• rs17361868
• NM_000138.5:c.1960+76G>A

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.1960+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,576,856 control chromosomes in the GnomAD database, including 2,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (278 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2688 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0450
• 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):

• 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=-0.85).
• BP6: Variant 15-48504949-C-T is Benign according to our data. Variant chr15-48504949-C-T is described in ClinVar as Benign. ClinVar VariationId is 674484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.1960+76G>A		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.1960+76G>A		intron	N/A	NP_001393645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.1960+76G>A		intron	N/A	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.1960+76G>A		intron	N/A	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.637-30299G>A		intron	N/A	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7595 AN: 152096 Hom.: 277 Cov.: 33

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0648

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0742

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.0607

GnomAD4 exome AF: 0.0578 AC: 82298 AN: 1424642 Hom.: 2688 AF XY: 0.0584 AC XY: 41521 AN XY: 711284

African (AFR) AF: 0.0102 AC: 334 AN: 32678

American (AMR) AF: 0.0823 AC: 3677 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 1524 AN: 25860

East Asian (EAS) AF: 0.139 AC: 5470 AN: 39460

South Asian (SAS) AF: 0.0837 AC: 7144 AN: 85354

European-Finnish (FIN) AF: 0.0796 AC: 4234 AN: 53168

Middle Eastern (MID) AF: 0.0395 AC: 225 AN: 5698

European-Non Finnish (NFE) AF: 0.0518 AC: 55889 AN: 1078654

Other (OTH) AF: 0.0643 AC: 3801 AN: 59112

GnomAD4 genome AF: 0.0499 AC: 7596 AN: 152214 Hom.: 278 Cov.: 33 AF XY: 0.0512 AC XY: 3812 AN XY: 74424

African (AFR) AF: 0.0132 AC: 549 AN: 41538

American (AMR) AF: 0.0648 AC: 991 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.152 AC: 787 AN: 5186

South Asian (SAS) AF: 0.0885 AC: 426 AN: 4816

European-Finnish (FIN) AF: 0.0742 AC: 787 AN: 10600

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0535 AC: 3641 AN: 67996

Other (OTH) AF: 0.0662 AC: 140 AN: 2114

Alfa AF: 0.0524 Hom.: 314

Bravo AF: 0.0473

Asia WGS AF: 0.164 AC: 570 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.31
PhyloP100		-0.045
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: rs17361868; hg19: chr15-48797146; COSMIC: COSV107345577;