19-8094478-G-C

Variant names:

• chr19-8094478-G-C
• rs7245429
• NM_032447.5:c.5873C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032447.5(FBN3):​c.5873C>G​(p.Pro1958Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P1958H) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.29
• Publications: 24 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

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.5873C>G	p.Pro1958Arg	missense	Exon 47 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.5873C>G	p.Pro1958Arg	missense	Exon 47 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.5873C>G	p.Pro1958Arg	missense	Exon 47 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.5873C>G	p.Pro1958Arg	missense	Exon 46 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.5873C>G	p.Pro1958Arg	missense	Exon 47 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249542 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00

GnomAD4 exome Cov.: 40

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 55926

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.67	P
Vest4		0.51
MutPred		0.50		Loss of disorder (P = 0.1333)
MVP		0.81
MPC		0.70
ClinPred		0.96	D
GERP RS		1.4
Varity_R		0.45
gMVP		0.77
Mutation Taster		=97/3	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: rs7245429; hg19: chr19-8159362;