22-45518715-C-T

Variant names:

• chr22-45518715-C-T
• rs202203586
• NM_006486.3:c.113C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006486.3(FBLN1):​c.113C>T​(p.Ala38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000695 in 1,611,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A38T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: FBLN1 NM_006486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• 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: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028130889).

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.113C>T	p.Ala38Val	missense	Exon 2 of 17	NP_006477.3
	FBLN1	NM_001996.4		c.113C>T	p.Ala38Val	missense	Exon 2 of 15	NP_001987.3
	FBLN1	NM_006485.4		c.113C>T	p.Ala38Val	missense	Exon 2 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.113C>T	p.Ala38Val	missense	Exon 2 of 17	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.113C>T	p.Ala38Val	missense	Exon 2 of 15	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.113C>T	p.Ala38Val	missense	Exon 2 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000106 AC: 26 AN: 244352 AF XY: 0.000129

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000623

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000665 AC: 97 AN: 1458852 Hom.: 0 Cov.: 32 AF XY: 0.0000855 AC XY: 62 AN XY: 725368

African (AFR) AF: 0.0000598 AC: 2 AN: 33428

American (AMR) AF: 0.0000225 AC: 1 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000328 AC: 28 AN: 85368

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110770

Other (OTH) AF: 0.000166 AC: 10 AN: 60286

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74484

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000157 AC: 19

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	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.081
Sift	Uncertain	0.017	D
Sift4G	Benign	0.094	T
Polyphen		0.87	P
Vest4		0.51
MVP		0.74
MPC		1.1
ClinPred		0.055	T
GERP RS		3.6
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.45
Mutation Taster		=87/13	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: rs202203586; hg19: chr22-45914595; COSMIC: COSV53048419; COSMIC: COSV53048419;