rs7246376

chr19-8138444-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032447.5(FBN3):c.986C>T(p.Pro329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,612,480 control chromosomes in the GnomAD database, including 40,854 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.23 (4531 hom., cov: 33)
  • Exomes 𝑓: 0.21 (36323 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.2250016E-5).
• BP6: Variant 19-8138444-G-A is Benign according to our data. Variant chr19-8138444-G-A is described in ClinVar as [Benign]. Clinvar id is 1600608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8138444-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.986C>T	p.Pro329Leu	missense_variant	9/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.986C>T	p.Pro329Leu	missense_variant	9/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.986C>T	p.Pro329Leu	missense_variant	8/63	1
FBN3	ENST00000601739.5	c.986C>T	p.Pro329Leu	missense_variant	9/64	1
FBN3	ENST00000651877.1	c.1112C>T	p.Pro371Leu	missense_variant	9/64			P1

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34856 AN: 152090 Hom.: 4517 Cov.: 33

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.266 AC: 65459 AN: 246014 Hom.: 10371 AF XY: 0.265 AC XY: 35428 AN XY: 133708

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.409

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.207 AC: 302638 AN: 1460272 Hom.: 36323 Cov.: 34 AF XY: 0.212 AC XY: 154353 AN XY: 726414

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.348

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.224

GnomAD4 genome AF: 0.229 AC: 34905 AN: 152208 Hom.: 4531 Cov.: 33 AF XY: 0.235 AC XY: 17509 AN XY: 74406

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.234

Alfa AF: 0.204 Hom.: 7199

Bravo AF: 0.240

TwinsUK AF: 0.173 AC: 642

ALSPAC AF: 0.180 AC: 692

ESP6500AA AF: 0.254 AC: 1120

ESP6500EA AF: 0.184 AC: 1579

ExAC AF: 0.260 AC: 31605

Asia WGS AF: 0.454 AC: 1576 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.191

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FBN3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	11
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.000052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.058	T;T;T
Polyphen		0.031	B;B;B
Vest4		0.063
MPC		0.20
ClinPred		0.0034	T
GERP RS		2.0
Varity_R		0.028
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs7246376; hg19: chr19-8203328; COSMIC: COSV54456294;