19-8096013-G-C

Variant names:

• chr19-8096013-G-C
• rs12150963
• NM_032447.5:c.5607C>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.5607C>G​(p.Asn1869Lys) variant causes a missense change. The variant allele was found at a frequency of 0.133 in 1,613,168 control chromosomes in the GnomAD database, including 16,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1397 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14616 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.12
• Publications: 17 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=0.0037261546).
• BP6: Variant 19-8096013-G-C is Benign according to our data. Variant chr19-8096013-G-C is described in ClinVar as Benign. ClinVar VariationId is 1537877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	NM_032447.5	MANE Select	c.5607C>G	p.Asn1869Lys	missense	Exon 45 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.5607C>G	p.Asn1869Lys	missense	Exon 45 of 64	NP_001308360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.5607C>G	p.Asn1869Lys	missense	Exon 45 of 64	ENSP00000470498.1
	FBN3	ENST00000270509.6	TSL:1	c.5607C>G	p.Asn1869Lys	missense	Exon 44 of 63	ENSP00000270509.2
	FBN3	ENST00000601739.5	TSL:1	c.5607C>G	p.Asn1869Lys	missense	Exon 45 of 64	ENSP00000472324.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18018 AN: 152074 Hom.: 1393 Cov.: 33

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.150 AC: 37721 AN: 251302 AF XY: 0.147

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.249

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.135 AC: 197306 AN: 1460974 Hom.: 14616 Cov.: 32 AF XY: 0.135 AC XY: 97970 AN XY: 726828

African (AFR) AF: 0.0258 AC: 865 AN: 33476

American (AMR) AF: 0.249 AC: 11145 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0915 AC: 2390 AN: 26130

East Asian (EAS) AF: 0.260 AC: 10323 AN: 39668

South Asian (SAS) AF: 0.121 AC: 10472 AN: 86236

European-Finnish (FIN) AF: 0.177 AC: 9465 AN: 53392

Middle Eastern (MID) AF: 0.0907 AC: 523 AN: 5768

European-Non Finnish (NFE) AF: 0.130 AC: 144368 AN: 1111232

Other (OTH) AF: 0.128 AC: 7755 AN: 60358

GnomAD4 genome AF: 0.118 AC: 18031 AN: 152194 Hom.: 1397 Cov.: 33 AF XY: 0.122 AC XY: 9053 AN XY: 74390

African (AFR) AF: 0.0338 AC: 1406 AN: 41540

American (AMR) AF: 0.208 AC: 3180 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.261 AC: 1347 AN: 5154

South Asian (SAS) AF: 0.108 AC: 522 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2061 AN: 10582

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8811 AN: 68014

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.118 Hom.: 955

Bravo AF: 0.118

TwinsUK AF: 0.143 AC: 529

ALSPAC AF: 0.128 AC: 495

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.133 AC: 1141

ExAC AF: 0.140 AC: 17006

Asia WGS AF: 0.156 AC: 539 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.118

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
PhyloP100		7.1
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.36
Sift	Benign	0.31	T
Sift4G	Benign	0.24	T
Polyphen		0.33	B
Vest4		0.24
MutPred		0.34		Gain of methylation at N1869 (P = 0.0022)
MPC		0.57
ClinPred		0.057	T
GERP RS		3.7
Varity_R		0.41
gMVP		0.71
Mutation Taster		=99/1	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: rs12150963; hg19: chr19-8160897; COSMIC: COSV54458703;