dbSNP rs559662894: FBLN1:p.Ala24Ala (chr22-45503057-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006486.3(FBLN1):c.72G>A(p.Ala24Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,247,188 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 6 hom. )

Consequence

FBLN1
NM_006486.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.110

Publications

1 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 22-45503057-G-A is Benign according to our data. Variant chr22-45503057-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.11 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0093 (1413/151854) while in subpopulation AFR AF = 0.0315 (1306/41500). AF 95% confidence interval is 0.0301. There are 20 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBLN1	NM_006486.3	MANE Select	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 17	NP_006477.3
FBLN1	NM_001996.4		c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 15	NP_001987.3
FBLN1	NM_006485.4		c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 15	NP_006476.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 17	ENSP00000331544.6	P23142-1
FBLN1	ENST00000262722.11	TSL:1	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 15	ENSP00000262722.7	P23142-4
FBLN1	ENST00000442170.6	TSL:1	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 15	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1410

AN:

151746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00322

Gnomad ASJ

AF:

0.00694

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000295

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00197

AC:

AN:

9648

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.0366

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00703

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000509

Gnomad OTH exome

AF:

0.00633

GnomAD4 exome

AF:

0.00109

AC:

1194

AN:

1095334

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

544

AN XY:

522814

show subpopulations

African (AFR)

AF:

0.0305

AC:

696

AN:

22788

American (AMR)

AF:

0.00315

AC:

AN:

9844

Ashkenazi Jewish (ASJ)

AF:

0.00855

AC:

126

AN:

14738

East Asian (EAS)

AF:

0.00

AC:

AN:

25980

South Asian (SAS)

AF:

0.000159

AC:

AN:

25084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21860

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

3164

European-Non Finnish (NFE)

AF:

0.000210

AC:

195

AN:

928194

Other (OTH)

AF:

0.00293

AC:

128

AN:

43682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

118

178

237

296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00930

AC:

1413

AN:

151854

Hom.:

Cov.:

AF XY:

0.00899

AC XY:

667

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.0315

AC:

1306

AN:

41500

American (AMR)

AF:

0.00321

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00694

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000295

AC:

AN:

67850

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00555

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00291

AC:

AN:

3446

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.11

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over