chr22-45518791-C-T

Variant names:

• chr22-45518791-C-T
• rs147045275
• NM_006486.3:c.185+4C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006486.3(FBLN1):​c.185+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,602,454 control chromosomes in the GnomAD database, including 4 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 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FBLN1 NM_006486.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006927
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.27
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-45518791-C-T is Benign according to our data. Variant chr22-45518791-C-T is described in ClinVar as Benign. ClinVar VariationId is 787509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBLN1	NM_006486.3	MANE Select	c.185+4C>T		splice_region intron	N/A	NP_006477.3
	FBLN1	NM_001996.4		c.185+4C>T		splice_region intron	N/A	NP_001987.3
	FBLN1	NM_006485.4		c.185+4C>T		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+4C>T		splice_region intron	N/A	ENSP00000331544.6	P23142-1
	FBLN1	ENST00000262722.11	TSL:1	c.185+4C>T		splice_region intron	N/A	ENSP00000262722.7	P23142-4
	FBLN1	ENST00000442170.6	TSL:1	c.185+4C>T		splice_region intron	N/A	ENSP00000393812.2	P23142-3

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00946

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000639 AC: 148 AN: 231528 AF XY: 0.000504

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000578

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000267 AC: 387 AN: 1450152 Hom.: 1 Cov.: 31 AF XY: 0.000236 AC XY: 170 AN XY: 720612

African (AFR) AF: 0.00862 AC: 286 AN: 33166

American (AMR) AF: 0.000666 AC: 29 AN: 43546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52826

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000235 AC: 26 AN: 1105654

Other (OTH) AF: 0.000734 AC: 44 AN: 59982

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74468

African (AFR) AF: 0.00953 AC: 396 AN: 41568

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

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	-0.64
CADD	Benign	0.19
DANN	Benign	0.92
PhyloP100		-5.3
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.022
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: rs147045275; hg19: chr22-45914671;