rs12162237

chr19-8142186-G-Achr19-8142186-G-T

Variant summary

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

The NM_032447.5(FBN3):c.542-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,484,270 control chromosomes in the GnomAD database, including 181,385 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 0.53 (22400 hom., cov: 32)
  • Exomes 𝑓: 0.48 (158985 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.542-49C>T		intron_variant		ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.542-49C>T		intron_variant		1	NM_032447.5
FBN3	ENST00000270509.6	c.542-49C>T		intron_variant		1
FBN3	ENST00000601739.5	c.542-49C>T		intron_variant		1
FBN3	ENST00000651877.1	c.542-49C>T		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81240 AN: 151940 Hom.: 22372 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.531 AC: 86682 AN: 163326 Hom.: 23336 AF XY: 0.535 AC XY: 47375 AN XY: 88610

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.580

Gnomad ASJ exome AF: 0.496

Gnomad EAS exome AF: 0.490

Gnomad SAS exome AF: 0.681

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.485 AC: 645915 AN: 1332212 Hom.: 158985 Cov.: 21 AF XY: 0.490 AC XY: 322560 AN XY: 657818

Gnomad4 AFR exome AF: 0.671

Gnomad4 AMR exome AF: 0.575

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.680

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.460

Gnomad4 OTH exome AF: 0.510

GnomAD4 genome AF: 0.535 AC: 81326 AN: 152058 Hom.: 22400 Cov.: 32 AF XY: 0.537 AC XY: 39922 AN XY: 74312

Gnomad4 AFR AF: 0.662

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.684

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.525

Alfa AF: 0.496 Hom.: 3513

Bravo AF: 0.544

Asia WGS AF: 0.637 AC: 2214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	1.1
Dann	Benign	0.63

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: rs12162237; hg19: chr19-8207070; COSMIC: COSV54470205;