19-8065983-G-T

Position:

• chr19-8065983-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032447.5(FBN3):​c.8366C>A​(p.Pro2789Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,612,228 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (15 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0380

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052331984).
• BP6: Variant 19-8065983-G-T is Benign according to our data. Variant chr19-8065983-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 729472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.8366C>A	p.Pro2789Gln	missense_variant	64/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.8366C>A	p.Pro2789Gln	missense_variant	64/64	1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6	c.8366C>A	p.Pro2789Gln	missense_variant	63/63	1		ENSP00000270509
FBN3	ENST00000601739.5	c.8366C>A	p.Pro2789Gln	missense_variant	64/64	1		ENSP00000472324
FBN3	ENST00000651877.1	c.8492C>A	p.Pro2831Gln	missense_variant	64/64			ENSP00000498507	P1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152242 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00279 AC: 692 AN: 247826 Hom.: 5 AF XY: 0.00289 AC XY: 390 AN XY: 134736

Gnomad AFR exome AF: 0.000761

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00674

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00308 AC: 4500 AN: 1459868 Hom.: 15 Cov.: 31 AF XY: 0.00301 AC XY: 2189 AN XY: 726080

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000708

Gnomad4 NFE exome AF: 0.00344

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152360 Hom.: 2 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74502

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00345

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00326 Hom.: 3

Bravo AF: 0.00233

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00293 AC: 355

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00504

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	FBN3: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

FBN3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.29
DANN	Benign	0.66
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.45	.;.;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.39	.;N;.
REVEL	Benign	0.092
Sift	Benign	0.57	.;T;.
Sift4G	Benign	0.45	T;T;T
Polyphen		0.011	B;B;B
Vest4		0.10
MVP		0.40
MPC		0.18
ClinPred		0.000032	T
GERP RS		-5.0
Varity_R		0.024
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35794930; hg19: chr19-8130867;