19-8096566-C-T

Position:

• chr19-8096566-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_032447.5(FBN3):​c.5417G>A​(p.Arg1806Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,610,228 control chromosomes in the GnomAD database, including 39,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3072 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36506 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.25

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

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-8096566-C-T is Benign according to our data. Variant chr19-8096566-C-T is described in ClinVar as [Benign]. Clinvar id is 1567977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8096566-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.5417G>A	p.Arg1806Gln	missense_variant	44/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.5417G>A	p.Arg1806Gln	missense_variant	44/64	1	NM_032447.5	ENSP00000470498.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29805 AN: 151938 Hom.: 3065 Cov.: 31

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.212 AC: 52636 AN: 248090 Hom.: 5868 AF XY: 0.216 AC XY: 29005 AN XY: 134002

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.231

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.222 AC: 323939 AN: 1458170 Hom.: 36506 Cov.: 34 AF XY: 0.223 AC XY: 161428 AN XY: 725164

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.196 AC: 29838 AN: 152058 Hom.: 3072 Cov.: 31 AF XY: 0.195 AC XY: 14502 AN XY: 74334

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.210

Alfa AF: 0.221 Hom.: 6951

Bravo AF: 0.195

TwinsUK AF: 0.221 AC: 820

ALSPAC AF: 0.221 AC: 851

ESP6500AA AF: 0.153 AC: 673

ESP6500EA AF: 0.227 AC: 1952

ExAC AF: 0.212 AC: 25716

Asia WGS AF: 0.206 AC: 719 AN: 3478

EpiCase AF: 0.235

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

FBN3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.73	.;.;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Benign	0.19
Sift	Benign	0.21	.;T;.
Sift4G	Benign	0.30	T;T;T
Polyphen		0.017	B;B;B
Vest4		0.072
MPC		0.28
ClinPred		0.019	T
GERP RS		-1.5
Varity_R		0.064
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3829817; hg19: chr19-8161450; COSMIC: COSV54459509;