rs1250204

chr2-215379109-T-C

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -0.163

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FN1	NM_212482.4	c.5622+21A>G		intron_variant		ENST00000354785.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FN1	ENST00000354785.11	c.5622+21A>G		intron_variant		1	NM_212482.4	P1

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

GnomAD3 exomes AF: 0.955 AC: 239972 AN: 251240 Hom.: 114700 AF XY: 0.955 AC XY: 129706 AN XY: 135778

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 SAS exome AF: 0.938

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

Gnomad4 AFR exome AF: 0.881

Gnomad4 AMR exome AF: 0.966

Gnomad4 ASJ exome AF: 0.947

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.939

Gnomad4 FIN exome AF: 0.966

Gnomad4 NFE exome AF: 0.958

Gnomad4 OTH exome AF: 0.951

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

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.962

Gnomad4 ASJ AF: 0.949

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.944

Gnomad4 FIN AF: 0.972

Gnomad4 NFE AF: 0.955

Gnomad4 OTH AF: 0.940

Alfa AF: 0.940 Hom.: 16964

Bravo AF: 0.936

Asia WGS AF: 0.967 AC: 3361 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Glomerulopathy with fibronectin deposits 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Spondylometaphyseal dysplasia - Sutcliffe type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.3
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1250204; hg19: chr2-216243832;