chr22-45503026-T-C

Variant names:

• chr22-45503026-T-C
• NM_006486.3:c.41T>C

Variant summary

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

The NM_006486.3(FBLN1):​c.41T>C​(p.Leu14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.793
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27745152).

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.41T>C	p.Leu14Pro	missense	Exon 1 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.41T>C	p.Leu14Pro	missense	Exon 1 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.41T>C	p.Leu14Pro	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.41T>C	p.Leu14Pro	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.41T>C	p.Leu14Pro	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.41T>C	p.Leu14Pro	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1099648 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 526964

African (AFR) AF: 0.00 AC: 0 AN: 22716

American (AMR) AF: 0.00 AC: 0 AN: 10356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14854

East Asian (EAS) AF: 0.00 AC: 0 AN: 25660

South Asian (SAS) AF: 0.00 AC: 0 AN: 26072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3040

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 931302

Other (OTH) AF: 0.00 AC: 0 AN: 43712

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.79
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.27
Sift	Benign	0.086	T
Sift4G	Uncertain	0.053	T
Polyphen		0.085	B
Vest4		0.26
MutPred		0.61		Gain of loop (P = 0.0079)
MVP		0.59
MPC		0.63
ClinPred		0.13	T
GERP RS		0.055
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.50
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr22-45898906;