NM_006486.3:c.113C>G

Variant names:

• chr22-45518715-C-G
• rs202203586
• NM_006486.3:c.113C>G

Variant summary

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

The NM_006486.3(FBLN1):​c.113C>G​(p.Ala38Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A38V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

Genes affected

FBLN1 (HGNC:3600): (fibulin 1) Fibulin 1 is a secreted glycoprotein that becomes incorporated into a fibrillar extracellular matrix. Calcium-binding is apparently required to mediate its binding to laminin and nidogen. It mediates platelet adhesion via binding fibrinogen. Four splice variants which differ in the 3' end have been identified. Each variant encodes a different isoform, but no functional distinctions have been identified among the four variants. [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=0.19178501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN1	NM_006486.3	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 17	ENST00000327858.11	NP_006477.3
FBLN1	NM_001996.4	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 15		NP_001987.3
FBLN1	NM_006485.4	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 15		NP_006476.3
FBLN1	NM_006487.3	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 15		NP_006478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN1	ENST00000327858.11	c.113C>G	p.Ala38Gly	missense_variant	Exon 2 of 17	1	NM_006486.3	ENSP00000331544.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458854 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725368

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;T;.;.;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	.;.;.;L;L;L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.10	T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		0.71, 0.56, 0.73	.;.;P;P;P;.;.
Vest4		0.23, 0.24, 0.21
MutPred		0.53		.;Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);
MVP		0.71
MPC		1.2
ClinPred		0.52	D
GERP RS		3.6
Varity_R		0.070
gMVP		0.39

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: rs202203586; hg19: chr22-45914595;