15-48456716-C-T

Variant names:

• chr15-48456716-C-T
• rs140649
• NM_000138.5:c.5343G>A

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.5343G>A​(p.Val1781Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,613,812 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1781V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (31 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 1.24
• Publications: 8 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=-0.26).
• BP6: Variant 15-48456716-C-T is Benign according to our data. Variant chr15-48456716-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00553 (842/152282) while in subpopulation NFE AF = 0.00889 (605/68018). AF 95% confidence interval is 0.00831. There are 5 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,Unknown,AR 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.5343G>A	p.Val1781Val	synonymous	Exon 44 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.5343G>A	p.Val1781Val	synonymous	Exon 43 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.5343G>A	p.Val1781Val	synonymous	Exon 44 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.5343G>A		non_coding_transcript_exon	Exon 44 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.*1106G>A		non_coding_transcript_exon	Exon 19 of 31	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152164 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00483 AC: 1212 AN: 251168 AF XY: 0.00499

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00449

Gnomad NFE exome AF: 0.00778

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00674 AC: 9851 AN: 1461530 Hom.: 31 Cov.: 32 AF XY: 0.00660 AC XY: 4797 AN XY: 727086

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.00407 AC: 182 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86256

European-Finnish (FIN) AF: 0.00459 AC: 245 AN: 53388

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00795 AC: 8843 AN: 1111712

Other (OTH) AF: 0.00568 AC: 343 AN: 60378

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152282 Hom.: 5 Cov.: 32 AF XY: 0.00537 AC XY: 400 AN XY: 74450

African (AFR) AF: 0.00149 AC: 62 AN: 41566

American (AMR) AF: 0.00419 AC: 64 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00434 AC: 46 AN: 10610

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00889 AC: 605 AN: 68018

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00682 Hom.: 7

Bravo AF: 0.00505

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00688

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	4	Familial thoracic aortic aneurysm and aortic dissection (4)
-	-	3	Marfan syndrome (3)
-	-	1	Acromicric dysplasia (1)
-	-	1	Connective tissue disorder (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	-0.26
CADD	Benign	5.8
DANN	Benign	0.70
PhyloP100		1.2
Mutation Taster		=97/3	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: rs140649; hg19: chr15-48748913;