rs12608849

chr19-8095450-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_032447.5(FBN3):c.5710C>T(p.Leu1904Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,136 control chromosomes in the GnomAD database, including 67,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1904P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5154 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61935 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.210

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.2354417E-4).
• BP6: Variant 19-8095450-G-A is Benign according to our data. Variant chr19-8095450-G-A is described in ClinVar as [Benign]. Clinvar id is 1562448.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-8095450-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.5710C>T	p.Leu1904Phe	missense_variant	46/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.5710C>T	p.Leu1904Phe	missense_variant	46/64	1	NM_032447.5

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36089 AN: 151878 Hom.: 5142 Cov.: 32

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.306 AC: 76956 AN: 251238 Hom.: 13001 AF XY: 0.310 AC XY: 42059 AN XY: 135816

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.351

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.422

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.284 AC: 414952 AN: 1461140 Hom.: 61935 Cov.: 34 AF XY: 0.288 AC XY: 209193 AN XY: 726914

Gnomad4 AFR exome AF: 0.0827

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.336

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.238 AC: 36106 AN: 151996 Hom.: 5154 Cov.: 32 AF XY: 0.247 AC XY: 18372 AN XY: 74306

Gnomad4 AFR AF: 0.0889

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.464

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.225

Alfa AF: 0.263 Hom.: 14091

Bravo AF: 0.220

TwinsUK AF: 0.262 AC: 971

ALSPAC AF: 0.283 AC: 1090

ESP6500AA AF: 0.0937 AC: 413

ESP6500EA AF: 0.253 AC: 2173

ExAC AF: 0.302 AC: 36644

Asia WGS AF: 0.428 AC: 1489 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	9.9
Dann	Benign	0.25
DEOGEN2	Benign	0.095	T;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.091	N
MetaRNN	Benign	0.00092	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.18	N;N;N
MutationTaster	Benign	0.91	P
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.059	B;B;B
Vest4		0.045
MPC		0.23
ClinPred		0.0010	T
GERP RS		-0.66
Varity_R		0.044
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12608849; hg19: chr19-8160334; COSMIC: COSV54455347;