chr19-8091482-T-G

Variant names:

• chr19-8091482-T-G
• rs17202741
• NM_032447.5:c.6014A>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.6014A>C​(p.Asn2005Thr) 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. 13/22 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. N2005S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.356
• Publications: 4 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=0.24467477).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.6014A>C	p.Asn2005Thr	missense_variant	Exon 48 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.6014A>C	p.Asn2005Thr	missense_variant	Exon 48 of 64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.6014A>C	p.Asn2005Thr	missense_variant	Exon 47 of 63	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.6014A>C	p.Asn2005Thr	missense_variant	Exon 48 of 64	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.6140A>C	p.Asn2047Thr	missense_variant	Exon 48 of 64			ENSP00000498507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000196 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T
Eigen	Benign	-0.076
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.73	.;.;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	0.64	N;N;N
PhyloP100		0.36
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	.;D;.
REVEL	Uncertain	0.34
Sift	Benign	0.26	.;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.24
MutPred		0.26		Gain of catalytic residue at N2005 (P = 0.0587);Gain of catalytic residue at N2005 (P = 0.0587);Gain of catalytic residue at N2005 (P = 0.0587);
MVP		0.74
MPC		0.69
ClinPred		0.95	D
GERP RS		2.3
Varity_R		0.30
gMVP		0.61
Mutation Taster		=92/8	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: rs17202741; hg19: chr19-8156366;