19-8112061-T-C

Variant names:

• chr19-8112061-T-C
• rs4804063
• NM_032447.5:c.3877A>G

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.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. 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 (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
• Publications: 20 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=0.001069516).
• BP6: Variant 19-8112061-T-C is Benign according to our data. Variant chr19-8112061-T-C is described in ClinVar as Benign. ClinVar VariationId is 1600962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 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.3877A>G	p.Ser1293Gly	missense	Exon 31 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.3877A>G	p.Ser1293Gly	missense	Exon 31 of 64	NP_001308360.1	Q75N90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.3877A>G	p.Ser1293Gly	missense	Exon 31 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.3877A>G	p.Ser1293Gly	missense	Exon 30 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.3877A>G	p.Ser1293Gly	missense	Exon 31 of 64	ENSP00000472324.1	Q75N90

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

GnomAD2 exomes AF: 0.253 AC: 63554 AN: 251100 AF XY: 0.251

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 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

African (AFR) AF: 0.278 AC: 9299 AN: 33448

American (AMR) AF: 0.322 AC: 14369 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4831 AN: 26102

East Asian (EAS) AF: 0.307 AC: 12179 AN: 39660

South Asian (SAS) AF: 0.361 AC: 31155 AN: 86200

European-Finnish (FIN) AF: 0.278 AC: 14815 AN: 53344

Middle Eastern (MID) AF: 0.165 AC: 953 AN: 5762

European-Non Finnish (NFE) AF: 0.182 AC: 201880 AN: 1111100

Other (OTH) AF: 0.215 AC: 12960 AN: 60340

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

African (AFR) AF: 0.276 AC: 11336 AN: 41114

American (AMR) AF: 0.264 AC: 4006 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3466

East Asian (EAS) AF: 0.365 AC: 1863 AN: 5104

South Asian (SAS) AF: 0.402 AC: 1914 AN: 4756

European-Finnish (FIN) AF: 0.291 AC: 3055 AN: 10490

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.179 AC: 12119 AN: 67834

Other (OTH) AF: 0.201 AC: 424 AN: 2106

Alfa AF: 0.190 Hom.: 14998

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.39
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.080
MPC		0.17
ClinPred		0.0054	T
GERP RS		-5.6
Varity_R		0.036
gMVP		0.30
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: rs4804063; hg19: chr19-8176945; COSMIC: COSV54453768; COSMIC: COSV54453768;