19-8066082-C-T

Variant names:

• chr19-8066082-C-T
• rs990576924
• NM_032447.5:c.8267G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032447.5(FBN3):​c.8267G>A​(p.Arg2756His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. R2756C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.465
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0549677).

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.8267G>A	p.Arg2756His	missense	Exon 64 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.8267G>A	p.Arg2756His	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.8267G>A	p.Arg2756His	missense	Exon 64 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.8267G>A	p.Arg2756His	missense	Exon 63 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.8267G>A	p.Arg2756His	missense	Exon 64 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249930 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000849 AC: 124 AN: 1461080 Hom.: 0 Cov.: 31 AF XY: 0.0000936 AC XY: 68 AN XY: 726856

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111952

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.29
DANN	Benign	0.83
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.47
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.20
Sift	Benign	0.45	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.031
MutPred		0.47		Gain of sheet (P = 0.0043)
MVP		0.45
MPC		0.24
ClinPred		0.038	T
GERP RS		-5.5
Varity_R		0.018
gMVP		0.40
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs990576924; hg19: chr19-8130966; COSMIC: COSV99495233; COSMIC: COSV99495233;