19-8096566-C-T

Variant names:

• chr19-8096566-C-T
• rs3829817
• NM_032447.5:c.5417G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 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. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1806W) has been classified as Uncertain significance.

• 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
• 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-8096566-C-T is Benign according to our data. Variant chr19-8096566-C-T is described in ClinVar as Benign. ClinVar VariationId is 1567977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.5417G>A	p.Arg1806Gln	missense_variant	Exon 44 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.5417G>A	p.Arg1806Gln	missense_variant	Exon 44 of 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

GnomAD2 exomes AF: 0.212 AC: 52636 AN: 248090 AF XY: 0.216

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 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

African (AFR) AF: 0.139 AC: 4643 AN: 33450

American (AMR) AF: 0.192 AC: 8565 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7041 AN: 25964

East Asian (EAS) AF: 0.201 AC: 7992 AN: 39666

South Asian (SAS) AF: 0.229 AC: 19699 AN: 85932

European-Finnish (FIN) AF: 0.202 AC: 10512 AN: 52024

Middle Eastern (MID) AF: 0.243 AC: 1382 AN: 5690

European-Non Finnish (NFE) AF: 0.226 AC: 250725 AN: 1110610

Other (OTH) AF: 0.222 AC: 13380 AN: 60282

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

African (AFR) AF: 0.143 AC: 5914 AN: 41484

American (AMR) AF: 0.200 AC: 3050 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 876 AN: 3468

East Asian (EAS) AF: 0.168 AC: 869 AN: 5160

South Asian (SAS) AF: 0.219 AC: 1052 AN: 4812

European-Finnish (FIN) AF: 0.195 AC: 2061 AN: 10594

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15300 AN: 67950

Other (OTH) AF: 0.210 AC: 443 AN: 2112

Alfa AF: 0.217 Hom.: 9093

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

FBN3-related disorder Benign:1

Oct 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		2.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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