19-8066028-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_032447.5(FBN3):c.8321G>A(p.Arg2774Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,613,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2774W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.120

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021845043).
• BP6: Variant 19-8066028-C-T is Benign according to our data. Variant chr19-8066028-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1098000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.8321G>A	p.Arg2774Gln	missense_variant	64/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.8321G>A	p.Arg2774Gln	missense_variant	64/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.8321G>A	p.Arg2774Gln	missense_variant	63/63	1
FBN3	ENST00000601739.5	c.8321G>A	p.Arg2774Gln	missense_variant	64/64	1
FBN3	ENST00000651877.1	c.8447G>A	p.Arg2816Gln	missense_variant	64/64			P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000683 AC: 17 AN: 248832 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135116

Gnomad AFR exome AF: 0.000816

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 31 AN XY: 726684

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74506

Gnomad4 AFR AF: 0.000817

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

See cases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 15, 2019

ACMG classification criteria: PM2, BP1, BP4 -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.80
Dann	Benign	0.76
DEOGEN2	Benign	0.017	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.39	N;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.048
MVP		0.48
MPC		0.22
ClinPred		0.0019	T
GERP RS		-0.39
Varity_R		0.026
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139098536; hg19: chr19-8130912; COSMIC: COSV53664929; COSMIC: COSV53664929;