rs4684968

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-13629276-T-A
• chr3-13629276-T-C
• chr3-13629276-T-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>A​(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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN2	NM_001004019.2	c.2826T>A	p.Phe942Leu	missense_variant	Exon 13 of 18	ENST00000404922.8	NP_001004019.1
FBLN2	NM_001165035.2	c.2826T>A	p.Phe942Leu	missense_variant	Exon 13 of 18		NP_001158507.1
FBLN2	NM_001998.3	c.2685T>A	p.Phe895Leu	missense_variant	Exon 12 of 17		NP_001989.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN2	ENST00000404922.8	c.2826T>A	p.Phe942Leu	missense_variant	Exon 13 of 18	5	NM_001004019.2	ENSP00000384169.3
FBLN2	ENST00000295760.11	c.2685T>A	p.Phe895Leu	missense_variant	Exon 12 of 17	1		ENSP00000295760.7
FBLN2	ENST00000492059.5	c.2826T>A	p.Phe942Leu	missense_variant	Exon 13 of 18	2		ENSP00000420042.1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458080 Hom.: 0 Cov.: 69 AF XY: 0.00 AC XY: 0 AN XY: 725146

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110698

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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	0.39	N
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.040	.;N;.
PhyloP100		-0.34
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Uncertain	0.57
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		1.0	D;P;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;