rs76711905

Variant names:

• chr22-45518661-C-T
• rs76711905
• NM_006486.3:c.80-21C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006486.3(FBLN1):​c.80-21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,575,144 control chromosomes in the GnomAD database, including 4,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (374 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4083 hom.)
• Consequence: FBLN1 NM_006486.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0660
• 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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 22-45518661-C-T is Benign according to our data. Variant chr22-45518661-C-T is described in ClinVar as Benign. ClinVar VariationId is 1260958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

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.80-21C>T		intron	N/A	NP_006477.3
	FBLN1	NM_001996.4		c.80-21C>T		intron	N/A	NP_001987.3
	FBLN1	NM_006485.4		c.80-21C>T		intron	N/A	NP_006476.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN1	ENST00000327858.11	TSL:1 MANE Select	c.80-21C>T		intron	N/A	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.80-21C>T		intron	N/A	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.80-21C>T		intron	N/A	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9769 AN: 152120 Hom.: 374 Cov.: 32

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0570 AC: 11320 AN: 198528 AF XY: 0.0559

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.00219

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.0552

GnomAD4 exome AF: 0.0722 AC: 102674 AN: 1422906 Hom.: 4083 Cov.: 30 AF XY: 0.0706 AC XY: 49779 AN XY: 705218

African (AFR) AF: 0.0507 AC: 1651 AN: 32566

American (AMR) AF: 0.0323 AC: 1286 AN: 39822

Ashkenazi Jewish (ASJ) AF: 0.0585 AC: 1487 AN: 25416

East Asian (EAS) AF: 0.00212 AC: 80 AN: 37754

South Asian (SAS) AF: 0.0254 AC: 2067 AN: 81220

European-Finnish (FIN) AF: 0.106 AC: 5441 AN: 51342

Middle Eastern (MID) AF: 0.0316 AC: 181 AN: 5732

European-Non Finnish (NFE) AF: 0.0796 AC: 86770 AN: 1090088

Other (OTH) AF: 0.0629 AC: 3711 AN: 58966

GnomAD4 genome AF: 0.0642 AC: 9773 AN: 152238 Hom.: 374 Cov.: 32 AF XY: 0.0637 AC XY: 4745 AN XY: 74440

African (AFR) AF: 0.0526 AC: 2187 AN: 41540

American (AMR) AF: 0.0432 AC: 660 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3472

East Asian (EAS) AF: 0.00250 AC: 13 AN: 5190

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4820

European-Finnish (FIN) AF: 0.112 AC: 1185 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0773 AC: 5255 AN: 67998

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0617 Hom.: 135

Bravo AF: 0.0590

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.89
PhyloP100		-0.066
PromoterAI		-0.0024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76711905; hg19: chr22-45914541;