rs774851476

Variant names:

• chr15-48481723-G-A
• rs774851476
• NM_000138.5:c.3896C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP6_Very_Strong BS1

The NM_000138.5(FBN1):​c.3896C>T​(p.Thr1299Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1299T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 8.05
• Publications: 3 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 -9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000138.5
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Weill-Marchesani syndrome 2, dominant, Acromicric dysplasia, isolated ectopia lentis, progeroid and marfanoid aspect-lipodystrophy syndrome, Marfan syndrome, stiff skin syndrome, Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection, ectopia lentis 1, isolated, autosomal dominant, Weill-Marchesani syndrome, neonatal Marfan syndrome, geleophysic dysplasia.
• BP6: Variant 15-48481723-G-A is Benign according to our data. Variant chr15-48481723-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 316375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000643 (94/1461540) while in subpopulation AMR AF = 0.00177 (79/44722). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.3896C>T	p.Thr1299Met	missense	Exon 32 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3896C>T	p.Thr1299Met	missense	Exon 31 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.3896C>T	p.Thr1299Met	missense	Exon 32 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3896C>T		non_coding_transcript_exon	Exon 32 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3896C>T		non_coding_transcript_exon	Exon 32 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000294 AC: 74 AN: 251336 AF XY: 0.000214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461540 Hom.: 0 Cov.: 30 AF XY: 0.0000536 AC XY: 39 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00177 AC: 79 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111738

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.000459 AC: 7 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	Marfan syndrome (2)
-	-	2	not specified (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	not provided (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		8.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.74
MutPred		0.71		Loss of methylation at K1300 (P = 0.0416)
MVP		0.94
MPC		1.4
ClinPred		0.19	T
GERP RS		5.4
Mutation Taster		=27/73	disease causing

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: rs774851476; hg19: chr15-48773920;