rs3813774

Variant names:

• chr19-8131615-G-A
• rs3813774
• NM_032447.5:c.1929C>T
• FBN3 p.Cys643Cys

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032447.5(FBN3):​c.1929C>T​(p.Cys643Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,614,004 control chromosomes in the GnomAD database, including 5,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1087 hom., cov: 33)
  • Exomes 𝑓: 0.068 (4536 hom.)
• Consequence: FBN3 NM_032447.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.19
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-8131615-G-A is Benign according to our data. Variant chr19-8131615-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 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.1929C>T	p.Cys643Cys	synonymous	Exon 15 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.1929C>T	p.Cys643Cys	synonymous	Exon 15 of 64	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.1929C>T	p.Cys643Cys	synonymous	Exon 15 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.1929C>T	p.Cys643Cys	synonymous	Exon 14 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.1929C>T	p.Cys643Cys	synonymous	Exon 15 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15311 AN: 152158 Hom.: 1087 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0980

GnomAD2 exomes AF: 0.0765 AC: 19208 AN: 251008 AF XY: 0.0734

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0598

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0609

Gnomad OTH exome AF: 0.0699

GnomAD4 exome AF: 0.0685 AC: 100073 AN: 1461728 Hom.: 4536 Cov.: 65 AF XY: 0.0678 AC XY: 49301 AN XY: 727144

African (AFR) AF: 0.201 AC: 6722 AN: 33476

American (AMR) AF: 0.0487 AC: 2179 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 1433 AN: 26128

East Asian (EAS) AF: 0.245 AC: 9714 AN: 39698

South Asian (SAS) AF: 0.0600 AC: 5173 AN: 86234

European-Finnish (FIN) AF: 0.0294 AC: 1569 AN: 53400

Middle Eastern (MID) AF: 0.111 AC: 639 AN: 5768

European-Non Finnish (NFE) AF: 0.0613 AC: 68162 AN: 1111918

Other (OTH) AF: 0.0742 AC: 4482 AN: 60388

GnomAD4 genome AF: 0.101 AC: 15330 AN: 152276 Hom.: 1087 Cov.: 33 AF XY: 0.0987 AC XY: 7349 AN XY: 74468

African (AFR) AF: 0.190 AC: 7913 AN: 41546

American (AMR) AF: 0.0643 AC: 984 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1110 AN: 5160

South Asian (SAS) AF: 0.0626 AC: 302 AN: 4826

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10628

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0631 AC: 4293 AN: 68024

Other (OTH) AF: 0.0970 AC: 205 AN: 2114

Alfa AF: 0.0773 Hom.: 2543

Bravo AF: 0.109

Asia WGS AF: 0.105 AC: 368 AN: 3478

EpiCase AF: 0.0654

EpiControl AF: 0.0715

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	FBN3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.9
DANN	Benign	0.51
PhyloP100		3.2
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3813774;

hg19: chr19-8196499;

COSMIC: COSV54455857;