19-8118987-G-A

Variant names:

• chr19-8118987-G-A
• rs35579498
• NM_032447.5:c.3247C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032447.5(FBN3):​c.3247C>T​(p.Arg1083Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,609,962 control chromosomes in the GnomAD database, including 3,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1083Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (375 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2936 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.94
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031781197).
• BP6: Variant 19-8118987-G-A is Benign according to our data. Variant chr19-8118987-G-A is described in ClinVar as Benign. ClinVar VariationId is 1540834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 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.3247C>T	p.Arg1083Trp	missense	Exon 26 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.3247C>T	p.Arg1083Trp	missense	Exon 26 of 64	NP_001308360.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.3247C>T	p.Arg1083Trp	missense	Exon 26 of 64	ENSP00000470498.1
	FBN3	ENST00000270509.6	TSL:1	c.3247C>T	p.Arg1083Trp	missense	Exon 25 of 63	ENSP00000270509.2
	FBN3	ENST00000601739.5	TSL:1	c.3247C>T	p.Arg1083Trp	missense	Exon 26 of 64	ENSP00000472324.1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7519 AN: 152160 Hom.: 371 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0816

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0367

Gnomad OTH AF: 0.0667

GnomAD2 exomes AF: 0.0713 AC: 17874 AN: 250778 AF XY: 0.0667

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0786

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0483 AC: 70358 AN: 1457684 Hom.: 2936 Cov.: 31 AF XY: 0.0479 AC XY: 34675 AN XY: 724258

African (AFR) AF: 0.0114 AC: 381 AN: 33424

American (AMR) AF: 0.190 AC: 8498 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 702 AN: 26108

East Asian (EAS) AF: 0.206 AC: 8144 AN: 39598

South Asian (SAS) AF: 0.0481 AC: 4140 AN: 86118

European-Finnish (FIN) AF: 0.0738 AC: 3926 AN: 53186

Middle Eastern (MID) AF: 0.0528 AC: 304 AN: 5760

European-Non Finnish (NFE) AF: 0.0371 AC: 41127 AN: 1108738

Other (OTH) AF: 0.0521 AC: 3136 AN: 60138

GnomAD4 genome AF: 0.0494 AC: 7528 AN: 152278 Hom.: 375 Cov.: 32 AF XY: 0.0530 AC XY: 3944 AN XY: 74470

African (AFR) AF: 0.0140 AC: 584 AN: 41582

American (AMR) AF: 0.141 AC: 2160 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.183 AC: 949 AN: 5174

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4830

European-Finnish (FIN) AF: 0.0816 AC: 866 AN: 10618

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0367 AC: 2496 AN: 68018

Other (OTH) AF: 0.0655 AC: 138 AN: 2106

Alfa AF: 0.0430 Hom.: 759

Bravo AF: 0.0549

TwinsUK AF: 0.0396 AC: 147

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.0387 AC: 333

ExAC AF: 0.0632 AC: 7670

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FBN3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.039	B
Vest4		0.38
MPC		0.68
ClinPred		0.086	T
GERP RS		0.39
Varity_R		0.80
gMVP		0.73
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: rs35579498; hg19: chr19-8183871; COSMIC: COSV54457918;