chr19-8094478-G-T

Variant names:

• chr19-8094478-G-T
• rs7245429
• NM_032447.5:c.5873C>A

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.5873C>A​(p.Pro1958His) variant causes a missense change. The variant allele was found at a frequency of 0.422 in 1,612,292 control chromosomes in the GnomAD database, including 149,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12817 hom., cov: 34)
  • Exomes 𝑓: 0.43 (137098 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.29
• Publications: 24 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=2.5079229E-5).
• BP6: Variant 19-8094478-G-T is Benign according to our data. Variant chr19-8094478-G-T is described in ClinVar as Benign. ClinVar VariationId is 1297917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.5873C>A	p.Pro1958His	missense_variant	Exon 47 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.5873C>A	p.Pro1958His	missense_variant	Exon 47 of 64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.5873C>A	p.Pro1958His	missense_variant	Exon 46 of 63	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.5873C>A	p.Pro1958His	missense_variant	Exon 47 of 64	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.5999C>A	p.Pro2000His	missense_variant	Exon 47 of 64			ENSP00000498507.1

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59258 AN: 152012 Hom.: 12801 Cov.: 34

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.730

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.372

GnomAD2 exomes AF: 0.468 AC: 116676 AN: 249542 AF XY: 0.466

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.726

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.395

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.425 AC: 621061 AN: 1460162 Hom.: 137098 Cov.: 40 AF XY: 0.429 AC XY: 311466 AN XY: 726358

African (AFR) AF: 0.226 AC: 7552 AN: 33440

American (AMR) AF: 0.597 AC: 26599 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8963 AN: 26104

East Asian (EAS) AF: 0.707 AC: 28055 AN: 39654

South Asian (SAS) AF: 0.560 AC: 48223 AN: 86080

European-Finnish (FIN) AF: 0.514 AC: 27406 AN: 53332

Middle Eastern (MID) AF: 0.359 AC: 2070 AN: 5758

European-Non Finnish (NFE) AF: 0.403 AC: 447228 AN: 1110914

Other (OTH) AF: 0.414 AC: 24965 AN: 60314

GnomAD4 genome AF: 0.390 AC: 59296 AN: 152130 Hom.: 12817 Cov.: 34 AF XY: 0.402 AC XY: 29899 AN XY: 74382

African (AFR) AF: 0.233 AC: 9654 AN: 41510

American (AMR) AF: 0.498 AC: 7607 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1198 AN: 3472

East Asian (EAS) AF: 0.730 AC: 3776 AN: 5174

South Asian (SAS) AF: 0.589 AC: 2835 AN: 4816

European-Finnish (FIN) AF: 0.539 AC: 5702 AN: 10586

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27207 AN: 67976

Other (OTH) AF: 0.377 AC: 797 AN: 2112

Alfa AF: 0.395 Hom.: 55926

Bravo AF: 0.376

TwinsUK AF: 0.406 AC: 1504

ALSPAC AF: 0.413 AC: 1592

ESP6500AA AF: 0.235 AC: 1034

ESP6500EA AF: 0.387 AC: 3332

ExAC AF: 0.455 AC: 55211

Asia WGS AF: 0.600 AC: 2083 AN: 3478

EpiCase AF: 0.382

EpiControl AF: 0.381

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 21, 2020

GeneDx

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	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	0.021
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;.;T
MetaRNN	Benign	0.000025	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M;M;M
PhyloP100		5.3
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.8	.;D;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.010	.;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.96	D;D;D
Vest4		0.36
MPC		0.77
ClinPred		0.060	T
GERP RS		1.4
Varity_R		0.60
gMVP		0.71
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: rs7245429; hg19: chr19-8159362; COSMIC: COSV54470904; COSMIC: COSV54470904;