rs12981294

Positions:

• chr19-8091337-A-G

Variant summary

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

The NM_032447.5(FBN3):​c.6031+128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,287,608 control chromosomes in the GnomAD database, including 32,124 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 0.20 (3113 hom., cov: 32)
  • Exomes 𝑓: 0.22 (29011 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0130

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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.6031+128T>C		intron_variant		ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.6031+128T>C		intron_variant		1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.6031+128T>C		intron_variant		1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.6031+128T>C		intron_variant		1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.6157+128T>C		intron_variant				ENSP00000498507.1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30114 AN: 151214 Hom.: 3101 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.224 AC: 254291 AN: 1136280 Hom.: 29011 AF XY: 0.224 AC XY: 126979 AN XY: 567724

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.199 AC: 30156 AN: 151328 Hom.: 3113 Cov.: 32 AF XY: 0.197 AC XY: 14597 AN XY: 73978

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.208

Alfa AF: 0.228 Hom.: 4011

Bravo AF: 0.198

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.7
DANN	Benign	0.68

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: rs12981294; hg19: chr19-8156221;