chr3-13571436-A-G

Position:

• chr3-13571436-A-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN2	NM_001004019.2	c.1081A>G	p.Ser361Gly	missense_variant	2/18	ENST00000404922.8	NP_001004019.1
FBLN2	NM_001165035.2	c.1081A>G	p.Ser361Gly	missense_variant	2/18		NP_001158507.1
FBLN2	NM_001998.3	c.1081A>G	p.Ser361Gly	missense_variant	2/17		NP_001989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN2	ENST00000404922.8	c.1081A>G	p.Ser361Gly	missense_variant	2/18	5	NM_001004019.2	ENSP00000384169.3
FBLN2	ENST00000295760.11	c.1081A>G	p.Ser361Gly	missense_variant	2/17	1		ENSP00000295760.7
FBLN2	ENST00000492059.5	c.1081A>G	p.Ser361Gly	missense_variant	2/18	2		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

GnomAD3 exomes AF: 0.283 AC: 69284 AN: 245044 Hom.: 12632 AF XY: 0.278 AC XY: 37013 AN XY: 133134

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 SAS exome AF: 0.374

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

Gnomad4 AFR exome AF: 0.701

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.577

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.187

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.270

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

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.266

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.330

Alfa AF: 0.238 Hom.: 6553

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 v4.3

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;T
MetaRNN	Benign	0.0000027	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.6	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.027
MPC		0.11
ClinPred		0.00016	T
GERP RS		1.9
Varity_R		0.037
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs3732666; hg19: chr3-13612936; COSMIC: COSV55481423; COSMIC: COSV55481423;