chr22-45503017-C-A

Variant names:

• chr22-45503017-C-A
• rs1017133697
• NM_006486.3:c.32C>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.32C>A​(p.Pro11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,247,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0300
• 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=0.25621688).

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.32C>A	p.Pro11Gln	missense	Exon 1 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.32C>A	p.Pro11Gln	missense	Exon 1 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.32C>A	p.Pro11Gln	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.32C>A	p.Pro11Gln	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.32C>A	p.Pro11Gln	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.32C>A	p.Pro11Gln	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151396 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095858 Hom.: 0 Cov.: 30 AF XY: 0.00000190 AC XY: 1 AN XY: 525400

African (AFR) AF: 0.00 AC: 0 AN: 22566

American (AMR) AF: 0.00 AC: 0 AN: 10154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14548

East Asian (EAS) AF: 0.00 AC: 0 AN: 25356

South Asian (SAS) AF: 0.00 AC: 0 AN: 25520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2994

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 929500

Other (OTH) AF: 0.00 AC: 0 AN: 43486

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151396 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73962

African (AFR) AF: 0.0000484 AC: 2 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67818

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Synpolydactyly type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.030
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.036	D
Polyphen		0.54	P
Vest4		0.16
MutPred		0.52		Loss of helix (P = 0.0093)
MVP		0.56
MPC		0.36
ClinPred		0.26	T
GERP RS		-1.3
PromoterAI		-0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.089
gMVP		0.42
Mutation Taster		=86/14	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: rs1017133697; hg19: chr22-45898897;