rs17160151

chr19-8085509-C-T

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.6941G>A(p.Ser2314Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,594,920 control chromosomes in the GnomAD database, including 2,297 homozygotes. In-silico tool predicts 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 0.068 (1227 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (1070 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.977

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=0.0036964118).
• BP6: Variant 19-8085509-C-T is Benign according to our data. Variant chr19-8085509-C-T is described in ClinVar as [Benign]. Clinvar id is 1601594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.6941G>A	p.Ser2314Asn	missense_variant	56/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.6941G>A	p.Ser2314Asn	missense_variant	56/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.6941G>A	p.Ser2314Asn	missense_variant	55/63	1
FBN3	ENST00000601739.5	c.6941G>A	p.Ser2314Asn	missense_variant	56/64	1
FBN3	ENST00000651877.1	c.7067G>A	p.Ser2356Asn	missense_variant	56/64			P1

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10388 AN: 152128 Hom.: 1223 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0611

GnomAD3 exomes AF: 0.0176 AC: 3779 AN: 215246 Hom.: 358 AF XY: 0.0131 AC XY: 1534 AN XY: 117120

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.00897

GnomAD4 exome AF: 0.00753 AC: 10870 AN: 1442674 Hom.: 1070 Cov.: 32 AF XY: 0.00662 AC XY: 4739 AN XY: 715990

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0684 AC: 10419 AN: 152246 Hom.: 1227 Cov.: 32 AF XY: 0.0666 AC XY: 4958 AN XY: 74444

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0605

Alfa AF: 0.0146 Hom.: 343

Bravo AF: 0.0780

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.227 AC: 998

ESP6500EA AF: 0.00222 AC: 19

ExAC AF: 0.0203 AC: 2449

Asia WGS AF: 0.0150 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FBN3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 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	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.048	T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.56	D
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.5	M;M;M
MutationTaster	Benign	0.93	P
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.31
MPC		0.59
ClinPred		0.012	T
GERP RS		2.3
Varity_R		0.43
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17160151; hg19: chr19-8150393; COSMIC: COSV54466328; COSMIC: COSV54466328;