19-8065992-C-T

Variant names:

• chr19-8065992-C-T
• rs760179129
• NM_032447.5:c.8357G>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.8357G>A​(p.Gly2786Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,952 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. G2786S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.328
• 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=0.052482247).

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.8357G>A	p.Gly2786Asp	missense	Exon 64 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.8357G>A	p.Gly2786Asp	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.8357G>A	p.Gly2786Asp	missense	Exon 64 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.8357G>A	p.Gly2786Asp	missense	Exon 63 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.8357G>A	p.Gly2786Asp	missense	Exon 64 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152264 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: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 247998 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1460570 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726576

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52234

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111944

Other (OTH) AF: 0.0000994 AC: 6 AN: 60380

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152382 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74522

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.4
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.33
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.092
Sift	Benign	0.62	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.067
MVP		0.49
MPC		0.25
ClinPred		0.026	T
GERP RS		-0.90
Varity_R		0.037
gMVP		0.63
Mutation Taster		=98/2	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: rs760179129; hg19: chr19-8130876;