rs4804064

Variant names:

• chr19-8124051-G-A
• rs4804064
• NM_032447.5:c.2732-43C>T

Variant summary

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

The NM_032447.5(FBN3):​c.2732-43C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,532,368 control chromosomes in the GnomAD database, including 76,502 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 0.34 (9348 hom., cov: 32)
  • Exomes 𝑓: 0.31 (67154 hom.)
• Consequence: FBN3 NM_032447.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.44 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.2732-43C>T		intron	N/A	NP_115823.3
	FBN3	NM_001321431.2		c.2732-43C>T		intron	N/A	NP_001308360.1	Q75N90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.2732-43C>T		intron	N/A	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.2732-43C>T		intron	N/A	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.2732-43C>T		intron	N/A	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52190 AN: 151898 Hom.: 9332 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.346 AC: 73940 AN: 213540 AF XY: 0.344

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.400

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.308 AC: 424509 AN: 1380352 Hom.: 67154 Cov.: 22 AF XY: 0.310 AC XY: 213664 AN XY: 688266

African (AFR) AF: 0.402 AC: 12696 AN: 31584

American (AMR) AF: 0.388 AC: 15758 AN: 40608

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7568 AN: 25268

East Asian (EAS) AF: 0.314 AC: 11898 AN: 37884

South Asian (SAS) AF: 0.419 AC: 34673 AN: 82792

European-Finnish (FIN) AF: 0.390 AC: 20135 AN: 51602

Middle Eastern (MID) AF: 0.242 AC: 1367 AN: 5638

European-Non Finnish (NFE) AF: 0.289 AC: 302550 AN: 1047450

Other (OTH) AF: 0.311 AC: 17864 AN: 57526

GnomAD4 genome AF: 0.344 AC: 52245 AN: 152016 Hom.: 9348 Cov.: 32 AF XY: 0.351 AC XY: 26072 AN XY: 74330

African (AFR) AF: 0.405 AC: 16793 AN: 41450

American (AMR) AF: 0.352 AC: 5372 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1033 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1964 AN: 5152

South Asian (SAS) AF: 0.456 AC: 2199 AN: 4820

European-Finnish (FIN) AF: 0.420 AC: 4441 AN: 10582

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19436 AN: 67972

Other (OTH) AF: 0.299 AC: 631 AN: 2110

Alfa AF: 0.301 Hom.: 4071

Bravo AF: 0.337

Asia WGS AF: 0.432 AC: 1500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.95
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4804064; hg19: chr19-8188935; COSMIC: COSV54456228;