chr22-45503047-C-T

Variant names:

• chr22-45503047-C-T
• rs573558018
• NM_006486.3:c.62C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006486.3(FBLN1):​c.62C>T​(p.Ala21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,249,902 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.198
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0079521835).
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown,AR gene

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.62C>T	p.Ala21Val	missense	Exon 1 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.62C>T	p.Ala21Val	missense	Exon 1 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.62C>T	p.Ala21Val	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.62C>T	p.Ala21Val	missense	Exon 1 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.62C>T	p.Ala21Val	missense	Exon 1 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.62C>T	p.Ala21Val	missense	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 151746 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

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: 0.000959

GnomAD2 exomes AF: 0.000442 AC: 6 AN: 13562 AF XY: 0.000118

Gnomad AFR exome AF: 0.00833

Gnomad AMR exome AF: 0.00200

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: 0.000230 AC: 253 AN: 1098048 Hom.: 2 Cov.: 30 AF XY: 0.000223 AC XY: 117 AN XY: 524534

African (AFR) AF: 0.00835 AC: 191 AN: 22870

American (AMR) AF: 0.00117 AC: 12 AN: 10298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14906

East Asian (EAS) AF: 0.00 AC: 0 AN: 25970

South Asian (SAS) AF: 0.00 AC: 0 AN: 25654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22032

Middle Eastern (MID) AF: 0.000322 AC: 1 AN: 3106

European-Non Finnish (NFE) AF: 0.00000430 AC: 4 AN: 929478

Other (OTH) AF: 0.00103 AC: 45 AN: 43734

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151854 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74220

African (AFR) AF: 0.00749 AC: 311 AN: 41512

American (AMR) AF: 0.000983 AC: 15 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67844

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.00258

ExAC AF: 0.000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.20
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.18
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.097
MutPred		0.67		Gain of sheet (P = 0.0028)
MVP		0.63
MPC		0.38
ClinPred		0.016	T
GERP RS		1.7
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.33
Mutation Taster		=70/30	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: rs573558018; hg19: chr22-45898927;