5-128330633-G-T

Variant names:

• chr5-128330633-G-T
• rs1060503511
• NM_001999.4:c.4285C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_001999.4(FBN2):​c.4285C>A​(p.Pro1429Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1429L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.65
• Publications: 0 publications found

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

FBN2 Gene-Disease associations (from GenCC):

• congenital contractural arachnodactyly

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• carpal tunnel syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Franklin by Genoox
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• macular degeneration, early-onset

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 8 uncertain in NM_001999.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-128330633-G-T is Pathogenic according to our data. Variant chr5-128330633-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 411835.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4285C>A	p.Pro1429Thr	missense_variant	Exon 33 of 65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4132C>A	p.Pro1378Thr	missense_variant	Exon 32 of 64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4285C>A	p.Pro1429Thr	missense_variant	Exon 33 of 65	1	NM_001999.4	ENSP00000262464.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:1

Sep 13, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Family studies indicate this missense variant likely was not inherited from either parent (i.e. occurred de novo) in an individual with disease (Invitae database). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. This sequence change replaces proline with threonine at codon 1429 of the FBN2 protein (p.Pro1429Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. In summary, this variant is a novel missense change that was shown to arise de-novo in an affected individual and has an unknown effect on protein function. For these reasons it has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Benign	0.87
DEOGEN2	Uncertain	0.65	D;.;D;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.11	T;.;T;T;T
Sift4G	Benign	0.57	.;.;.;T;T
Polyphen		0.27	B;.;B;.;D
Vest4		0.61
MutPred		0.51		Gain of catalytic residue at P1429 (P = 0.0071);.;Gain of catalytic residue at P1429 (P = 0.0071);.;.;
MVP		0.70
MPC		0.88
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.24
gMVP		0.81
Mutation Taster		=59/41	disease causing (ClinVar)

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: rs1060503511; hg19: chr5-127666325;