NM_006486.3:c.74C>A

Variant names:

• chr22-45503059-C-A
• rs528661383
• NM_006486.3:c.74C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006486.3(FBLN1):​c.74C>A​(p.Ala25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A25V) 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: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.18
• Publications: 2 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4113966).

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.74C>A	p.Ala25Asp	missense	Exon 1 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.74C>A	p.Ala25Asp	missense	Exon 1 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.74C>A	p.Ala25Asp	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.74C>A	p.Ala25Asp	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.74C>A	p.Ala25Asp	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.74C>A	p.Ala25Asp	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 8396 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095020 Hom.: 0 Cov.: 30 AF XY: 0.00000191 AC XY: 1 AN XY: 522638

African (AFR) AF: 0.00 AC: 0 AN: 22760

American (AMR) AF: 0.000103 AC: 1 AN: 9678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14702

East Asian (EAS) AF: 0.00 AC: 0 AN: 25972

South Asian (SAS) AF: 0.00 AC: 0 AN: 25044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3160

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 928180

Other (OTH) AF: 0.00 AC: 0 AN: 43666

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.36
Sift	Benign	0.10	T
Sift4G	Uncertain	0.050	T
Polyphen		0.96	D
Vest4		0.33
MutPred		0.55		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.64
MPC		0.58
ClinPred		0.33	T
GERP RS		1.5
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.42
Mutation Taster		=78/22	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: rs528661383; hg19: chr22-45898939;