19-8066028-C-G

Variant names:

• chr19-8066028-C-G
• rs139098536
• NM_032447.5:c.8321G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032447.5(FBN3):​c.8321G>C​(p.Arg2774Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2774Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.120
• Publications: 7 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13375509).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. 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
	FBN3	NM_032447.5	MANE Select	c.8321G>C	p.Arg2774Pro	missense	Exon 64 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.8321G>C	p.Arg2774Pro	missense	Exon 64 of 64	NP_001308360.1	Q75N90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.8321G>C	p.Arg2774Pro	missense	Exon 64 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.8321G>C	p.Arg2774Pro	missense	Exon 63 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.8321G>C	p.Arg2774Pro	missense	Exon 64 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248832 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	3.4
DANN	Benign	0.94
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.12
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.12	B
Vest4		0.34
MutPred		0.52		Loss of MoRF binding (P = 0.0045)
MVP		0.67
MPC		0.33
ClinPred		0.061	T
GERP RS		-0.39
Varity_R		0.25
gMVP		0.80
Mutation Taster		=89/11	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: rs139098536; hg19: chr19-8130912;