19-8111756-C-T

Variant names:

• chr19-8111756-C-T
• rs12975322
• NM_032447.5:c.3976G>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.3976G>A​(p.Val1326Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,612,612 control chromosomes in the GnomAD database, including 50,968 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1326F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4972 hom., cov: 28)
  • Exomes 𝑓: 0.25 (45996 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.85
• Publications: 28 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=1.3646483E-4).
• BP6: Variant 19-8111756-C-T is Benign according to our data. Variant chr19-8111756-C-T is described in ClinVar as Benign. ClinVar VariationId is 1562437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 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.3976G>A	p.Val1326Ile	missense	Exon 32 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.3976G>A	p.Val1326Ile	missense	Exon 32 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.3976G>A	p.Val1326Ile	missense	Exon 32 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.3976G>A	p.Val1326Ile	missense	Exon 31 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.3976G>A	p.Val1326Ile	missense	Exon 32 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38087 AN: 151690 Hom.: 4946 Cov.: 28

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.275

GnomAD2 exomes AF: 0.264 AC: 66126 AN: 250556 AF XY: 0.258

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.361

Gnomad ASJ exome AF: 0.249

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.246 AC: 358730 AN: 1460804 Hom.: 45996 Cov.: 39 AF XY: 0.245 AC XY: 177800 AN XY: 726638

African (AFR) AF: 0.235 AC: 7858 AN: 33462

American (AMR) AF: 0.363 AC: 16230 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6627 AN: 26108

East Asian (EAS) AF: 0.470 AC: 18634 AN: 39670

South Asian (SAS) AF: 0.218 AC: 18762 AN: 86224

European-Finnish (FIN) AF: 0.216 AC: 11501 AN: 53360

Middle Eastern (MID) AF: 0.227 AC: 1306 AN: 5752

European-Non Finnish (NFE) AF: 0.236 AC: 262633 AN: 1111198

Other (OTH) AF: 0.252 AC: 15179 AN: 60346

GnomAD4 genome AF: 0.251 AC: 38155 AN: 151808 Hom.: 4972 Cov.: 28 AF XY: 0.250 AC XY: 18536 AN XY: 74176

African (AFR) AF: 0.240 AC: 9922 AN: 41370

American (AMR) AF: 0.327 AC: 4982 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 839 AN: 3470

East Asian (EAS) AF: 0.432 AC: 2205 AN: 5104

South Asian (SAS) AF: 0.198 AC: 951 AN: 4814

European-Finnish (FIN) AF: 0.224 AC: 2372 AN: 10570

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.237 AC: 16109 AN: 67914

Other (OTH) AF: 0.273 AC: 576 AN: 2110

Alfa AF: 0.242 Hom.: 23108

Bravo AF: 0.263

TwinsUK AF: 0.244 AC: 903

ALSPAC AF: 0.231 AC: 890

ESP6500AA AF: 0.256 AC: 1126

ESP6500EA AF: 0.242 AC: 2080

ExAC AF: 0.255 AC: 31005

Asia WGS AF: 0.311 AC: 1083 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.232

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	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.077
DANN	Benign	0.83
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.35	N
PhyloP100		-1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.15
Sift	Benign	0.53	T
Sift4G	Benign	0.086	T
Polyphen		0.56	P
Vest4		0.043
MPC		0.16
ClinPred		0.0029	T
GERP RS		1.7
Varity_R		0.021
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs12975322; hg19: chr19-8176640; COSMIC: COSV54453721;