19-8066122-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032447.5(FBN3):c.8227C>T(p.Arg2743Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R2743R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37778026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.8227C>T	p.Arg2743Cys	missense_variant	64/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.8227C>T	p.Arg2743Cys	missense_variant	64/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.8227C>T	p.Arg2743Cys	missense_variant	63/63	1
FBN3	ENST00000601739.5	c.8227C>T	p.Arg2743Cys	missense_variant	64/64	1
FBN3	ENST00000651877.1	c.8353C>T	p.Arg2785Cys	missense_variant	64/64			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249374 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461184 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with FBN3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2743 of the FBN3 protein (p.Arg2743Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	0.52	D
PrimateAI	Benign	0.25	T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.20
MutPred		0.54		Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);
MVP		0.83
MPC		0.64
ClinPred		0.84	D
GERP RS		2.2
Varity_R		0.14
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1294126203; hg19: chr19-8131006; COSMIC: COSV53663897; COSMIC: COSV53663897;