rs1250215

Variant names:

• chr2-215388316-G-C
• rs1250215
• NM_212482.4:c.4253-15C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-215388316-G-C
• chr2-215388316-G-T

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.4253-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 1,591,364 control chromosomes in the GnomAD database, including 295,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21816 hom., cov: 32)
  • Exomes 𝑓: 0.61 (273392 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0390
• Publications: 17 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=-0.83).
• BP6: Variant 2-215388316-G-C is Benign according to our data. Variant chr2-215388316-G-C is described in ClinVar as Benign. ClinVar VariationId is 1284045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 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.4253-15C>G		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.4253-15C>G		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.4253-15C>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.4253-15C>G		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.4253-15C>G		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.3980-15C>G		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77897 AN: 151976 Hom.: 21813 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.483

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.497

GnomAD2 exomes AF: 0.546 AC: 136948 AN: 250956 AF XY: 0.555

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.635

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.608 AC: 875270 AN: 1439270 Hom.: 273392 Cov.: 26 AF XY: 0.607 AC XY: 435728 AN XY: 717548

African (AFR) AF: 0.297 AC: 9750 AN: 32810

American (AMR) AF: 0.460 AC: 20565 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 12691 AN: 25982

East Asian (EAS) AF: 0.200 AC: 7889 AN: 39510

South Asian (SAS) AF: 0.558 AC: 47867 AN: 85794

European-Finnish (FIN) AF: 0.684 AC: 36392 AN: 53214

Middle Eastern (MID) AF: 0.450 AC: 2572 AN: 5718

European-Non Finnish (NFE) AF: 0.644 AC: 703602 AN: 1091918

Other (OTH) AF: 0.569 AC: 33942 AN: 59644

GnomAD4 genome AF: 0.512 AC: 77927 AN: 152094 Hom.: 21816 Cov.: 32 AF XY: 0.511 AC XY: 37993 AN XY: 74354

African (AFR) AF: 0.308 AC: 12777 AN: 41478

American (AMR) AF: 0.474 AC: 7253 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1676 AN: 3470

East Asian (EAS) AF: 0.221 AC: 1143 AN: 5180

South Asian (SAS) AF: 0.542 AC: 2612 AN: 4818

European-Finnish (FIN) AF: 0.686 AC: 7247 AN: 10568

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43506 AN: 67974

Other (OTH) AF: 0.492 AC: 1041 AN: 2114

Alfa AF: 0.502 Hom.: 2879

Bravo AF: 0.486

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	-0.83
CADD	Benign	7.9
DANN	Benign	0.44
PhyloP100		-0.039
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1250215; hg19: chr2-216253039; COSMIC: COSV60551687; COSMIC: COSV60551687;