19-8121635-A-G

Variant names:

• chr19-8121635-A-G
• rs4527136
• NM_032447.5:c.3083-249T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032447.5(FBN3):​c.3083-249T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 151,754 control chromosomes in the GnomAD database, including 34,982 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 0.67 (34982 hom., cov: 32)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.3083-249T>C		intron	N/A	NP_115823.3
	FBN3	NM_001321431.2		c.3083-249T>C		intron	N/A	NP_001308360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.3083-249T>C		intron	N/A	ENSP00000470498.1
	FBN3	ENST00000270509.6	TSL:1	c.3083-249T>C		intron	N/A	ENSP00000270509.2
	FBN3	ENST00000601739.5	TSL:1	c.3083-249T>C		intron	N/A	ENSP00000472324.1

Frequencies

GnomAD3 genomes AF: 0.667 AC: 101074 AN: 151636 Hom.: 34917 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.628

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.667 AC: 101204 AN: 151754 Hom.: 34982 Cov.: 32 AF XY: 0.673 AC XY: 49910 AN XY: 74122

African (AFR) AF: 0.845 AC: 34989 AN: 41394

American (AMR) AF: 0.713 AC: 10875 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1890 AN: 3468

East Asian (EAS) AF: 0.710 AC: 3647 AN: 5140

South Asian (SAS) AF: 0.719 AC: 3465 AN: 4816

European-Finnish (FIN) AF: 0.665 AC: 7011 AN: 10540

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.550 AC: 37307 AN: 67846

Other (OTH) AF: 0.630 AC: 1324 AN: 2100

Alfa AF: 0.581 Hom.: 110586

Bravo AF: 0.677

Asia WGS AF: 0.750 AC: 2608 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.35
DANN	Benign	0.28
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4527136; hg19: chr19-8186519;