rs33967815

Variant names:

• chr19-8103661-C-T
• rs33967815
• NM_032447.5:c.4840G>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.4840G>A​(p.Gly1614Ser) variant causes a missense change. The variant allele was found at a frequency of 0.287 in 1,612,494 control chromosomes in the GnomAD database, including 72,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4893 hom., cov: 31)
  • Exomes 𝑓: 0.29 (67163 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.59
• Publications: 21 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=0.0020065904).
• BP6: Variant 19-8103661-C-T is Benign according to our data. Variant chr19-8103661-C-T is described in ClinVar as Benign. ClinVar VariationId is 1598993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.322 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.4840G>A	p.Gly1614Ser	missense	Exon 39 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.4840G>A	p.Gly1614Ser	missense	Exon 39 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.4840G>A	p.Gly1614Ser	missense	Exon 39 of 64	ENSP00000470498.1
	FBN3	ENST00000270509.6	TSL:1	c.4840G>A	p.Gly1614Ser	missense	Exon 38 of 63	ENSP00000270509.2
	FBN3	ENST00000601739.5	TSL:1	c.4840G>A	p.Gly1614Ser	missense	Exon 39 of 64	ENSP00000472324.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34488 AN: 151834 Hom.: 4897 Cov.: 31

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.244 AC: 61177 AN: 251112 AF XY: 0.251

Gnomad AFR exome AF: 0.0778

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.0561

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.293 AC: 428578 AN: 1460542 Hom.: 67163 Cov.: 33 AF XY: 0.292 AC XY: 212467 AN XY: 726626

African (AFR) AF: 0.0749 AC: 2505 AN: 33456

American (AMR) AF: 0.152 AC: 6806 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8826 AN: 26092

East Asian (EAS) AF: 0.0568 AC: 2254 AN: 39672

South Asian (SAS) AF: 0.195 AC: 16772 AN: 86222

European-Finnish (FIN) AF: 0.255 AC: 13603 AN: 53326

Middle Eastern (MID) AF: 0.328 AC: 1887 AN: 5760

European-Non Finnish (NFE) AF: 0.323 AC: 358966 AN: 1110970

Other (OTH) AF: 0.281 AC: 16959 AN: 60344

GnomAD4 genome AF: 0.227 AC: 34478 AN: 151952 Hom.: 4893 Cov.: 31 AF XY: 0.221 AC XY: 16437 AN XY: 74250

African (AFR) AF: 0.0809 AC: 3355 AN: 41454

American (AMR) AF: 0.202 AC: 3076 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1226 AN: 3470

East Asian (EAS) AF: 0.0555 AC: 287 AN: 5172

South Asian (SAS) AF: 0.179 AC: 865 AN: 4822

European-Finnish (FIN) AF: 0.246 AC: 2592 AN: 10534

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22153 AN: 67944

Other (OTH) AF: 0.262 AC: 551 AN: 2106

Alfa AF: 0.293 Hom.: 24645

Bravo AF: 0.218

TwinsUK AF: 0.320 AC: 1185

ALSPAC AF: 0.318 AC: 1227

ESP6500AA AF: 0.0856 AC: 377

ESP6500EA AF: 0.337 AC: 2900

ExAC AF: 0.247 AC: 29969

Asia WGS AF: 0.126 AC: 437 AN: 3478

EpiCase AF: 0.338

EpiControl AF: 0.336

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	0.070
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.68	N
PhyloP100		5.6
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.37
MPC		0.65
ClinPred		0.019	T
GERP RS		3.6
Varity_R		0.49
gMVP		0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs33967815; hg19: chr19-8168545; COSMIC: COSV54459174; COSMIC: COSV54459174;