rs12608849

Variant names:

• chr19-8095450-G-A
• rs12608849
• NM_032447.5:c.5710C>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.5710C>T​(p.Leu1904Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,136 control chromosomes in the GnomAD database, including 67,089 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5154 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61935 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210
• Publications: 25 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=9.2354417E-4).
• BP6: Variant 19-8095450-G-A is Benign according to our data. Variant chr19-8095450-G-A is described in ClinVar as Benign. ClinVar VariationId is 1562448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.5710C>T	p.Leu1904Phe	missense_variant	Exon 46 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.5710C>T	p.Leu1904Phe	missense_variant	Exon 46 of 64	1	NM_032447.5	ENSP00000470498.1

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36089 AN: 151878 Hom.: 5142 Cov.: 32

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.306 AC: 76956 AN: 251238 AF XY: 0.310

Gnomad AFR exome AF: 0.0840

Gnomad AMR exome AF: 0.351

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.454

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.284 AC: 414952 AN: 1461140 Hom.: 61935 Cov.: 34 AF XY: 0.288 AC XY: 209193 AN XY: 726914

African (AFR) AF: 0.0827 AC: 2766 AN: 33462

American (AMR) AF: 0.340 AC: 15178 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6496 AN: 26104

East Asian (EAS) AF: 0.447 AC: 17732 AN: 39658

South Asian (SAS) AF: 0.420 AC: 36209 AN: 86216

European-Finnish (FIN) AF: 0.336 AC: 17952 AN: 53370

Middle Eastern (MID) AF: 0.244 AC: 1408 AN: 5766

European-Non Finnish (NFE) AF: 0.270 AC: 300614 AN: 1111532

Other (OTH) AF: 0.275 AC: 16597 AN: 60350

GnomAD4 genome AF: 0.238 AC: 36106 AN: 151996 Hom.: 5154 Cov.: 32 AF XY: 0.247 AC XY: 18372 AN XY: 74306

African (AFR) AF: 0.0889 AC: 3690 AN: 41496

American (AMR) AF: 0.278 AC: 4238 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 854 AN: 3460

East Asian (EAS) AF: 0.467 AC: 2415 AN: 5166

South Asian (SAS) AF: 0.464 AC: 2232 AN: 4808

European-Finnish (FIN) AF: 0.344 AC: 3623 AN: 10536

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18189 AN: 67952

Other (OTH) AF: 0.225 AC: 476 AN: 2112

Alfa AF: 0.259 Hom.: 26844

Bravo AF: 0.220

TwinsUK AF: 0.262 AC: 971

ALSPAC AF: 0.283 AC: 1090

ESP6500AA AF: 0.0937 AC: 413

ESP6500EA AF: 0.253 AC: 2173

ExAC AF: 0.302 AC: 36644

Asia WGS AF: 0.428 AC: 1489 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.9
DANN	Benign	0.25
DEOGEN2	Benign	0.095	T;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.37	.;.;T
MetaRNN	Benign	0.00092	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.18	N;N;N
PhyloP100		-0.21
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.49	.;N;.
REVEL	Benign	0.17
Sift	Benign	0.70	.;T;.
Sift4G	Benign	0.79	T;T;T
Polyphen		0.059	B;B;B
Vest4		0.045
MPC		0.23
ClinPred		0.0010	T
GERP RS		-0.66
Varity_R		0.044
gMVP		0.60
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12608849; hg19: chr19-8160334; COSMIC: COSV54455347;