rs1250204

Variant names:

• chr2-215379109-T-C
• rs1250204
• NM_212482.4:c.5622+21A>G

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.5622+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.955 in 1,609,764 control chromosomes in the GnomAD database, including 734,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67084 hom., cov: 32)
  • Exomes 𝑓: 0.96 (667137 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.163
• 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=-0.8).
• BP6: Variant 2-215379109-T-C is Benign according to our data. Variant chr2-215379109-T-C is described in ClinVar as Benign. ClinVar VariationId is 1250663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.5622+21A>G		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.5622+21A>G		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.5352+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.5622+21A>G		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.5622+21A>G		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.5349+21A>G		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142733 AN: 152114 Hom.: 67039 Cov.: 32

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.949

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.940

GnomAD2 exomes AF: 0.955 AC: 239972 AN: 251240 AF XY: 0.955

Gnomad AFR exome AF: 0.882

Gnomad AMR exome AF: 0.970

Gnomad ASJ exome AF: 0.948

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.968

Gnomad NFE exome AF: 0.957

Gnomad OTH exome AF: 0.955

GnomAD4 exome AF: 0.957 AC: 1394229 AN: 1457532 Hom.: 667137 Cov.: 31 AF XY: 0.956 AC XY: 693581 AN XY: 725460

African (AFR) AF: 0.881 AC: 29392 AN: 33364

American (AMR) AF: 0.966 AC: 43215 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.947 AC: 24716 AN: 26112

East Asian (EAS) AF: 1.00 AC: 39673 AN: 39682

South Asian (SAS) AF: 0.939 AC: 80887 AN: 86184

European-Finnish (FIN) AF: 0.966 AC: 51599 AN: 53416

Middle Eastern (MID) AF: 0.950 AC: 5469 AN: 5756

European-Non Finnish (NFE) AF: 0.958 AC: 1061978 AN: 1108074

Other (OTH) AF: 0.951 AC: 57300 AN: 60230

GnomAD4 genome AF: 0.938 AC: 142834 AN: 152232 Hom.: 67084 Cov.: 32 AF XY: 0.940 AC XY: 69951 AN XY: 74428

African (AFR) AF: 0.883 AC: 36677 AN: 41524

American (AMR) AF: 0.962 AC: 14710 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 3296 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5154 AN: 5160

South Asian (SAS) AF: 0.944 AC: 4553 AN: 4824

European-Finnish (FIN) AF: 0.972 AC: 10306 AN: 10608

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64996 AN: 68028

Other (OTH) AF: 0.940 AC: 1988 AN: 2114

Alfa AF: 0.940 Hom.: 16964

Bravo AF: 0.936

Asia WGS AF: 0.967 AC: 3361 AN: 3478

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	-0.80
CADD	Benign	1.3
DANN	Benign	0.55
PhyloP100		-0.16
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)		0.030		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: rs1250204; hg19: chr2-216243832;