rs3732666

Variant names:

• chr3-13571436-A-G
• rs3732666
• NM_001004019.2:c.1081A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-13571436-A-G
• chr3-13571436-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004019.2(FBLN2):​c.1081A>G​(p.Ser361Gly) 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 1,611,990 control chromosomes in the GnomAD database, including 61,824 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.36 (13404 hom., cov: 34)
  • Exomes 𝑓: 0.23 (48420 hom.)
• Consequence: FBLN2 NM_001004019.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.201
• Publications: 26 publications found

Genes affected

FBLN2 (HGNC:3601): (fibulin 2) This gene encodes an extracellular matrix protein, which belongs to the fibulin family. This protein binds various extracellular ligands and calcium. It may play a role during organ development, in particular, during the differentiation of heart, skeletal and neuronal structures. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FBLN2 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.7290948E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004019.2. 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
	FBLN2	NM_001004019.2	MANE Select	c.1081A>G	p.Ser361Gly	missense	Exon 2 of 18	NP_001004019.1
	FBLN2	NM_001165035.2		c.1081A>G	p.Ser361Gly	missense	Exon 2 of 18	NP_001158507.1
	FBLN2	NM_001998.3		c.1081A>G	p.Ser361Gly	missense	Exon 2 of 17	NP_001989.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	ENST00000404922.8	TSL:5 MANE Select	c.1081A>G	p.Ser361Gly	missense	Exon 2 of 18	ENSP00000384169.3
	FBLN2	ENST00000295760.11	TSL:1	c.1081A>G	p.Ser361Gly	missense	Exon 2 of 17	ENSP00000295760.7
	FBLN2	ENST00000492059.5	TSL:2	c.1081A>G	p.Ser361Gly	missense	Exon 2 of 18	ENSP00000420042.1

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54624 AN: 152056 Hom.: 13352 Cov.: 34

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.283 AC: 69284 AN: 245044 AF XY: 0.278

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.563

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.245

GnomAD4 exome AF: 0.234 AC: 341272 AN: 1459816 Hom.: 48420 Cov.: 36 AF XY: 0.236 AC XY: 171640 AN XY: 726052

African (AFR) AF: 0.701 AC: 23442 AN: 33442

American (AMR) AF: 0.252 AC: 11188 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6995 AN: 26068

East Asian (EAS) AF: 0.577 AC: 22820 AN: 39572

South Asian (SAS) AF: 0.376 AC: 32238 AN: 85826

European-Finnish (FIN) AF: 0.187 AC: 9907 AN: 53118

Middle Eastern (MID) AF: 0.281 AC: 1621 AN: 5762

European-Non Finnish (NFE) AF: 0.195 AC: 216763 AN: 1111246

Other (OTH) AF: 0.270 AC: 16298 AN: 60324

GnomAD4 genome AF: 0.360 AC: 54732 AN: 152174 Hom.: 13404 Cov.: 34 AF XY: 0.361 AC XY: 26845 AN XY: 74402

African (AFR) AF: 0.686 AC: 28490 AN: 41516

American (AMR) AF: 0.277 AC: 4243 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 922 AN: 3466

East Asian (EAS) AF: 0.558 AC: 2869 AN: 5144

South Asian (SAS) AF: 0.392 AC: 1890 AN: 4826

European-Finnish (FIN) AF: 0.179 AC: 1905 AN: 10616

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13429 AN: 67990

Other (OTH) AF: 0.330 AC: 697 AN: 2112

Alfa AF: 0.259 Hom.: 10974

Bravo AF: 0.381

TwinsUK AF: 0.189 AC: 700

ALSPAC AF: 0.195 AC: 753

ESP6500AA AF: 0.656 AC: 2822

ESP6500EA AF: 0.197 AC: 1671

ExAC AF: 0.289 AC: 35024

Asia WGS AF: 0.496 AC: 1722 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.20
DANN	Benign	0.31
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-0.20
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.13
Sift	Benign	0.58	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.11
ClinPred		0.00016	T
GERP RS		1.9
Varity_R		0.037
gMVP		0.24
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: rs3732666; hg19: chr3-13612936; COSMIC: COSV55481423; COSMIC: COSV55481423;