3-13629276-T-G

Variant names:

• chr3-13629276-T-G
• rs4684968
• NM_001004019.2:c.2826T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001004019.2(FBLN2):​c.2826T>G​(p.Phe942Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F942F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 36)
• Consequence: FBLN2 NM_001004019.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 17 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	NM_001004019.2	MANE Select	c.2826T>G	p.Phe942Leu	missense	Exon 13 of 18	NP_001004019.1
	FBLN2	NM_001165035.2		c.2826T>G	p.Phe942Leu	missense	Exon 13 of 18	NP_001158507.1
	FBLN2	NM_001998.3		c.2685T>G	p.Phe895Leu	missense	Exon 12 of 17	NP_001989.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN2	ENST00000404922.8	TSL:5 MANE Select	c.2826T>G	p.Phe942Leu	missense	Exon 13 of 18	ENSP00000384169.3
	FBLN2	ENST00000295760.11	TSL:1	c.2685T>G	p.Phe895Leu	missense	Exon 12 of 17	ENSP00000295760.7
	FBLN2	ENST00000492059.5	TSL:2	c.2826T>G	p.Phe942Leu	missense	Exon 13 of 18	ENSP00000420042.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	7.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.040	N
PhyloP100		-0.34
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.57
Sift	Benign	1.0	T
Sift4G	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.56
MVP		0.58
MPC		0.39
ClinPred		0.94	D
GERP RS		-1.6
Varity_R		0.25
gMVP		0.38
Mutation Taster		=68/32	polymorphism

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: rs4684968; hg19: chr3-13670776;