22-45503043-C-A

Variant names:

• chr22-45503043-C-A
• rs1434686879
• NM_006486.3:c.58C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006486.3(FBLN1):​c.58C>A​(p.Leu20Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000909 in 1,099,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. L20F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.356
• Publications: 0 publications found

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]

FBLN1 Gene-Disease associations (from GenCC):

• FBLN1-related developmental delay-central nervous system anomaly-syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• synpolydactyly type 2

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23050594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN1	NM_006486.3	MANE Select	c.58C>A	p.Leu20Ile	missense	Exon 1 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.58C>A	p.Leu20Ile	missense	Exon 1 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.58C>A	p.Leu20Ile	missense	Exon 1 of 15	NP_006476.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.58C>A	p.Leu20Ile	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.58C>A	p.Leu20Ile	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.58C>A	p.Leu20Ile	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.09e-7 AC: 1 AN: 1099572 Hom.: 0 Cov.: 30 AF XY: 0.00000190 AC XY: 1 AN XY: 525446

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22896

American (AMR) AF: 0.00 AC: 0 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14974

East Asian (EAS) AF: 0.00 AC: 0 AN: 25992

South Asian (SAS) AF: 0.00 AC: 0 AN: 25858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3090

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 930368

Other (OTH) AF: 0.00 AC: 0 AN: 43820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.36
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.12
Sift	Benign	0.24	T
Sift4G	Benign	0.10	T
Polyphen		0.036	B
Vest4		0.20
MutPred		0.67		Gain of sheet (P = 0.0266)
MVP		0.38
MPC		0.42
ClinPred		0.084	T
GERP RS		0.49
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.061
gMVP		0.23
Mutation Taster		=81/19	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: rs1434686879; hg19: chr22-45898923;