rs2430347

Variant names:

• chr14-91881336-A-C
• NM_006329.4:c.945T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-91881336-A-C
• chr14-91881336-A-G
• chr14-91881336-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006329.4(FBLN5):​c.945T>G​(p.Ile315Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I315I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBLN5 NM_006329.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.509

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.945T>G	p.Ile315Met	missense_variant	Exon 9 of 11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.945T>G	p.Ile315Met	missense_variant	Exon 9 of 11	1	NM_006329.4	ENSP00000345008.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.73
DANN	Benign	0.89
DEOGEN2	Benign	0.069	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.056	T;D;T
Sift4G	Uncertain	0.038	D;T;T
Polyphen		0.94	P;B;P
Vest4		0.37
MutPred		0.45		Gain of catalytic residue at I359 (P = 0.0256);.;.;
MVP		0.57
MPC		0.56
ClinPred		0.54	D
GERP RS		-11
Varity_R		0.10
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-92347680;