rs4804064

Positions:

• chr19-8124051-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032447.5(FBN3):​c.2732-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,532,368 control chromosomes in the GnomAD database, including 76,502 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9348 hom., cov: 32)
  • Exomes 𝑓: 0.31 (67154 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.2732-43C>T		intron_variant		ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.2732-43C>T		intron_variant		1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6	c.2732-43C>T		intron_variant		1		ENSP00000270509
FBN3	ENST00000601739.5	c.2732-43C>T		intron_variant		1		ENSP00000472324
FBN3	ENST00000651877.1	c.2858-43C>T		intron_variant				ENSP00000498507	P1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52190 AN: 151898 Hom.: 9332 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.293

GnomAD3 exomes AF: 0.346 AC: 73940 AN: 213540 Hom.: 13135 AF XY: 0.344 AC XY: 39890 AN XY: 116088

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.374

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.308 AC: 424509 AN: 1380352 Hom.: 67154 Cov.: 22 AF XY: 0.310 AC XY: 213664 AN XY: 688266

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.344 AC: 52245 AN: 152016 Hom.: 9348 Cov.: 32 AF XY: 0.351 AC XY: 26072 AN XY: 74330

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.299

Alfa AF: 0.298 Hom.: 1855

Bravo AF: 0.337

Asia WGS AF: 0.432 AC: 1500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4804064; hg19: chr19-8188935; COSMIC: COSV54456228;