rs8112525

Positions:

• chr19-8136167-T-C
• chr19-8136167-T-G

Variant summary

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

The NM_032447.5(FBN3):​c.1465+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,613,478 control chromosomes in the GnomAD database, including 676,152 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 0.92 (65027 hom., cov: 31)
  • Exomes 𝑓: 0.91 (611125 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.1465+23A>G		intron_variant		ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.1465+23A>G		intron_variant		1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6	c.1465+23A>G		intron_variant		1		ENSP00000270509
FBN3	ENST00000601739.5	c.1465+23A>G		intron_variant		1		ENSP00000472324
FBN3	ENST00000651877.1	c.1591+23A>G		intron_variant				ENSP00000498507	P1

Frequencies

GnomAD3 genomes AF: 0.924 AC: 140442 AN: 152072 Hom.: 64974 Cov.: 31

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.931

GnomAD3 exomes AF: 0.911 AC: 227768 AN: 250122 Hom.: 104061 AF XY: 0.910 AC XY: 123063 AN XY: 135258

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.941

Gnomad ASJ exome AF: 0.927

Gnomad EAS exome AF: 0.747

Gnomad SAS exome AF: 0.921

Gnomad FIN exome AF: 0.899

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.914 AC: 1335461 AN: 1461288 Hom.: 611125 Cov.: 81 AF XY: 0.914 AC XY: 664331 AN XY: 726942

Gnomad4 AFR exome AF: 0.958

Gnomad4 AMR exome AF: 0.938

Gnomad4 ASJ exome AF: 0.923

Gnomad4 EAS exome AF: 0.735

Gnomad4 SAS exome AF: 0.918

Gnomad4 FIN exome AF: 0.902

Gnomad4 NFE exome AF: 0.918

Gnomad4 OTH exome AF: 0.907

GnomAD4 genome AF: 0.924 AC: 140554 AN: 152190 Hom.: 65027 Cov.: 31 AF XY: 0.921 AC XY: 68526 AN XY: 74408

Gnomad4 AFR AF: 0.955

Gnomad4 AMR AF: 0.929

Gnomad4 ASJ AF: 0.924

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.915

Gnomad4 FIN AF: 0.887

Gnomad4 NFE AF: 0.922

Gnomad4 OTH AF: 0.931

Alfa AF: 0.919 Hom.: 87241

Bravo AF: 0.927

Asia WGS AF: 0.868 AC: 3021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.52

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: rs8112525; hg19: chr19-8201051;