rs17458018

Variant names:

• chr2-215420652-T-C
• rs17458018
• NM_212482.4:c.1675+21A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-215420652-T-C
• chr2-215420652-T-A

Variant summary

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

The NM_212482.4(FN1):​c.1675+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 1,613,784 control chromosomes in the GnomAD database, including 3,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (248 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3249 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.242
• Publications: 9 publications found

Genes affected

FN1 (HGNC:3778): (fibronectin 1) This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined. [provided by RefSeq, Jan 2016]

FN1 Gene-Disease associations (from GenCC):

• spondylometaphyseal dysplasia, 'corner fracture' type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• glomerulopathy with fibronectin deposits 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• fibronectin glomerulopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-215420652-T-C is Benign according to our data. Variant chr2-215420652-T-C is described in ClinVar as Benign. ClinVar VariationId is 1285279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212482.4. 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
	FN1	NM_212482.4	MANE Select	c.1675+21A>G		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.1675+21A>G		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.1675+21A>G		intron	N/A	NP_001352446.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FN1	ENST00000354785.11	TSL:1 MANE Select	c.1675+21A>G		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.1675+21A>G		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.1675+21A>G		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6913 AN: 152128 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0543

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0617

GnomAD2 exomes AF: 0.0594 AC: 14927 AN: 251390 AF XY: 0.0665

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0988

Gnomad EAS exome AF: 0.000761

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0629

Gnomad OTH exome AF: 0.0632

GnomAD4 exome AF: 0.0612 AC: 89480 AN: 1461538 Hom.: 3249 Cov.: 31 AF XY: 0.0642 AC XY: 46672 AN XY: 727072

African (AFR) AF: 0.0134 AC: 449 AN: 33476

American (AMR) AF: 0.0358 AC: 1601 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0946 AC: 2471 AN: 26126

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.137 AC: 11809 AN: 86254

European-Finnish (FIN) AF: 0.0302 AC: 1613 AN: 53408

Middle Eastern (MID) AF: 0.109 AC: 631 AN: 5766

European-Non Finnish (NFE) AF: 0.0603 AC: 67058 AN: 1111718

Other (OTH) AF: 0.0635 AC: 3833 AN: 60370

GnomAD4 genome AF: 0.0454 AC: 6915 AN: 152246 Hom.: 248 Cov.: 32 AF XY: 0.0453 AC XY: 3376 AN XY: 74452

African (AFR) AF: 0.0156 AC: 649 AN: 41550

American (AMR) AF: 0.0542 AC: 828 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0931 AC: 323 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.131 AC: 631 AN: 4814

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10622

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4022 AN: 68016

Other (OTH) AF: 0.0605 AC: 128 AN: 2114

Alfa AF: 0.0572 Hom.: 551

Bravo AF: 0.0431

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glomerulopathy with fibronectin deposits 2 (1)
-	-	1	Spondylometaphyseal dysplasia - Sutcliffe type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.94
DANN	Benign	0.59
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17458018; hg19: chr2-216285375; COSMIC: COSV60555046;