19-8085256-C-CACACAG

Variant names:

• chr19-8085256-C-CACACAG
• rs3222751
• NM_032447.5:c.7087+106_7087+107insCTGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032447.5(FBN3):​c.7087+106_7087+107insCTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 719,478 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.393
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.7087+106_7087+107insCTGTGT		intron_variant	Intron 56 of 63	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.7087+106_7087+107insCTGTGT		intron_variant	Intron 56 of 63	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.7087+106_7087+107insCTGTGT		intron_variant	Intron 55 of 62	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.7087+106_7087+107insCTGTGT		intron_variant	Intron 56 of 63	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.7213+106_7213+107insCTGTGT		intron_variant	Intron 56 of 63			ENSP00000498507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000278 AC: 2 AN: 719478 Hom.: 0 AF XY: 0.00000266 AC XY: 1 AN XY: 375682

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16476

American (AMR) AF: 0.00 AC: 0 AN: 20404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18916

East Asian (EAS) AF: 0.00 AC: 0 AN: 31534

South Asian (SAS) AF: 0.00 AC: 0 AN: 59076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2688

European-Non Finnish (NFE) AF: 0.00000402 AC: 2 AN: 497582

Other (OTH) AF: 0.00 AC: 0 AN: 35450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3222751; hg19: chr19-8150140;