chr22-45518795-T-C

Variant names:

• chr22-45518795-T-C
• rs78488153
• NM_006486.3:c.185+8T>C

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.185+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,597,416 control chromosomes in the GnomAD database, including 13,408 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4603 hom., cov: 32)
  • Exomes 𝑓: 0.093 (8805 hom.)
• Consequence: FBLN1 NM_006486.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008021
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.213
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-45518795-T-C is Benign according to our data. Variant chr22-45518795-T-C is described in ClinVar as Benign. ClinVar VariationId is 1286401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 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.185+8T>C		splice_region intron	N/A	NP_006477.3
	FBLN1	NM_001996.4		c.185+8T>C		splice_region intron	N/A	NP_001987.3
	FBLN1	NM_006485.4		c.185+8T>C		splice_region 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.185+8T>C		splice_region intron	N/A	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.185+8T>C		splice_region intron	N/A	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.185+8T>C		splice_region intron	N/A	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27925 AN: 152116 Hom.: 4583 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.0718

Gnomad EAS AF: 0.0510

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.0981 AC: 22276 AN: 226968 AF XY: 0.0907

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0679

Gnomad EAS exome AF: 0.0393

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0838

Gnomad OTH exome AF: 0.0770

GnomAD4 exome AF: 0.0933 AC: 134869 AN: 1445182 Hom.: 8805 Cov.: 30 AF XY: 0.0908 AC XY: 65207 AN XY: 717998

African (AFR) AF: 0.452 AC: 14935 AN: 33056

American (AMR) AF: 0.0562 AC: 2420 AN: 43060

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1732 AN: 25812

East Asian (EAS) AF: 0.0639 AC: 2492 AN: 39004

South Asian (SAS) AF: 0.0640 AC: 5357 AN: 83712

European-Finnish (FIN) AF: 0.112 AC: 5879 AN: 52650

Middle Eastern (MID) AF: 0.0535 AC: 308 AN: 5758

European-Non Finnish (NFE) AF: 0.0869 AC: 95791 AN: 1102336

Other (OTH) AF: 0.0996 AC: 5955 AN: 59794

GnomAD4 genome AF: 0.184 AC: 28001 AN: 152234 Hom.: 4603 Cov.: 32 AF XY: 0.180 AC XY: 13382 AN XY: 74436

African (AFR) AF: 0.446 AC: 18488 AN: 41492

American (AMR) AF: 0.0881 AC: 1348 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 249 AN: 3470

East Asian (EAS) AF: 0.0510 AC: 264 AN: 5180

South Asian (SAS) AF: 0.0671 AC: 324 AN: 4826

European-Finnish (FIN) AF: 0.116 AC: 1233 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0845 AC: 5748 AN: 68032

Other (OTH) AF: 0.140 AC: 295 AN: 2110

Alfa AF: 0.123 Hom.: 1433

Bravo AF: 0.192

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.1
DANN	Benign	0.88
PhyloP100		-0.21
PromoterAI		-0.0057	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000080
dbscSNV1_RF	Benign	0.070
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: rs78488153; hg19: chr22-45914675;