Genetic Variant FBLN1:c.79+13C>A (chr22-45503077-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006486.3(FBLN1):c.79+13C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000925 in 1,080,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.3e-7 ( 0 hom. )

Consequence

FBLN1
NM_006486.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.641

Publications

0 publications found

Variant links:

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

FBLN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FBLN1	NM_006486.3	MANE Select	c.79+13C>A	intron	N/A	NP_006477.3
FBLN1	NM_001996.4		c.79+13C>A	intron	N/A	NP_001987.3
FBLN1	NM_006485.4		c.79+13C>A	intron	N/A	NP_006476.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.79+13C>A	intron	N/A	ENSP00000331544.6	P23142-1
FBLN1	ENST00000262722.11	TSL:1	c.79+13C>A	intron	N/A	ENSP00000262722.7	P23142-4
FBLN1	ENST00000442170.6	TSL:1	c.79+13C>A	intron	N/A	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.25e-7

AC:

AN:

1080594

Hom.:

Cov.:

AF XY:

0.00000195

AC XY:

AN XY:

513484

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22462

American (AMR)

AF:

0.00

AC:

AN:

8492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14086

East Asian (EAS)

AF:

0.00

AC:

AN:

25696

South Asian (SAS)

AF:

0.0000437

AC:

AN:

22866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3212

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

919484

Other (OTH)

AF:

0.00

AC:

AN:

43050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.2

(source)

DANN

Benign

0.92

PhyloP100

-0.64

PromoterAI

-0.17

Neutral

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over