chr19-8066097-C-G

Position:

• chr19-8066097-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032447.5(FBN3):​c.8252G>C​(p.Arg2751Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2751C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.35

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.8252G>C	p.Arg2751Pro	missense_variant	64/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.8252G>C	p.Arg2751Pro	missense_variant	64/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.8252G>C	p.Arg2751Pro	missense_variant	63/63	1
FBN3	ENST00000601739.5	c.8252G>C	p.Arg2751Pro	missense_variant	64/64	1
FBN3	ENST00000651877.1	c.8378G>C	p.Arg2793Pro	missense_variant	64/64			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250056 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461166 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000333 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.8252G>C (p.R2751P) alteration is located in exon 63 (coding exon 63) of the FBN3 gene. This alteration results from a G to C substitution at nucleotide position 8252, causing the arginine (R) at amino acid position 2751 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 25, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2751 of the FBN3 protein (p.Arg2751Pro). 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: "Probably 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 (rs764446097, gnomAD 0.002%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.64	.;.;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	0.94	D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.4	.;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.018	.;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.94	P;P;P
Vest4		0.53
MutPred		0.63		Loss of MoRF binding (P = 0.0016);Loss of MoRF binding (P = 0.0016);Loss of MoRF binding (P = 0.0016);
MVP		0.77
MPC		0.89
ClinPred		0.97	D
GERP RS		-3.8
Varity_R		0.67
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs764446097; hg19: chr19-8130981;