rs4804063

Positions:

• chr19-8112061-T-C
• chr19-8112061-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032447.5(FBN3):​c.3877A>G​(p.Ser1293Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,611,874 control chromosomes in the GnomAD database, including 38,890 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1293N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4617 hom., cov: 28)
  • Exomes 𝑓: 0.21 (34273 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.390

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001069516).
• BP6: Variant 19-8112061-T-C is Benign according to our data. Variant chr19-8112061-T-C is described in ClinVar as [Benign]. Clinvar id is 1600962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8112061-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.3877A>G	p.Ser1293Gly	missense_variant	31/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.3877A>G	p.Ser1293Gly	missense_variant	31/64	1	NM_032447.5	ENSP00000470498
FBN3	ENST00000270509.6	c.3877A>G	p.Ser1293Gly	missense_variant	30/63	1		ENSP00000270509
FBN3	ENST00000601739.5	c.3877A>G	p.Ser1293Gly	missense_variant	31/64	1		ENSP00000472324
FBN3	ENST00000651877.1	c.4003A>G	p.Ser1335Gly	missense_variant	31/64			ENSP00000498507	P1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35633 AN: 151130 Hom.: 4602 Cov.: 28

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.253 AC: 63554 AN: 251100 Hom.: 9093 AF XY: 0.251 AC XY: 34022 AN XY: 135710

Gnomad AFR exome AF: 0.275

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.207 AC: 302441 AN: 1460626 Hom.: 34273 Cov.: 34 AF XY: 0.210 AC XY: 152784 AN XY: 726656

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.322

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.236 AC: 35663 AN: 151248 Hom.: 4617 Cov.: 28 AF XY: 0.245 AC XY: 18087 AN XY: 73870

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.201

Alfa AF: 0.183 Hom.: 7179

Bravo AF: 0.231

TwinsUK AF: 0.186 AC: 688

ALSPAC AF: 0.186 AC: 715

ESP6500AA AF: 0.272 AC: 1200

ESP6500EA AF: 0.172 AC: 1480

ExAC AF: 0.252 AC: 30587

Asia WGS AF: 0.395 AC: 1370 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.171

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.6
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.64	.;.;T
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	.;N;.
REVEL	Benign	0.12
Sift	Benign	0.37	.;T;.
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.080
MPC		0.17
ClinPred		0.0054	T
GERP RS		-5.6
Varity_R		0.036
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs4804063; hg19: chr19-8176945; COSMIC: COSV54453768; COSMIC: COSV54453768;