2-215361861-GTTTTT-GTTTTTT

Variant names:

• chr2-215361861-G-GT
• rs55953250
• NM_212482.4:c.7362+107dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_212482.4(FN1):​c.7362+107dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,046,854 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.032 (0 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.478
• Publications: 0 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]

ATIC (HGNC:794): (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]

ATIC Gene-Disease associations (from GenCC):

• AICA-ribosiduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00215 (315/146802) while in subpopulation EAS AF = 0.0101 (51/5038). AF 95% confidence interval is 0.00791. There are 2 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.7362+107dupA		intron_variant	Intron 45 of 45	ENST00000354785.11	NP_997647.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FN1	ENST00000354785.11	c.7362+107_7362+108insA		intron_variant	Intron 45 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 314 AN: 146718 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.000644

Gnomad FIN AF: 0.000846

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000665

Gnomad OTH AF: 0.00199

GnomAD4 exome AF: 0.0323 AC: 29080 AN: 900052 Hom.: 0 Cov.: 18 AF XY: 0.0319 AC XY: 14114 AN XY: 442604

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0376 AC: 749 AN: 19898

American (AMR) AF: 0.0321 AC: 620 AN: 19286

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 504 AN: 15610

East Asian (EAS) AF: 0.0310 AC: 688 AN: 22210

South Asian (SAS) AF: 0.0253 AC: 1165 AN: 45966

European-Finnish (FIN) AF: 0.0263 AC: 808 AN: 30750

Middle Eastern (MID) AF: 0.0338 AC: 86 AN: 2548

European-Non Finnish (NFE) AF: 0.0330 AC: 23305 AN: 706930

Other (OTH) AF: 0.0313 AC: 1155 AN: 36854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00215 AC: 315 AN: 146802 Hom.: 2 Cov.: 32 AF XY: 0.00228 AC XY: 163 AN XY: 71502

African (AFR) AF: 0.00440 AC: 177 AN: 40210

American (AMR) AF: 0.00184 AC: 27 AN: 14654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.0101 AC: 51 AN: 5038

South Asian (SAS) AF: 0.000646 AC: 3 AN: 4646

European-Finnish (FIN) AF: 0.000846 AC: 8 AN: 9452

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000665 AC: 44 AN: 66204

Other (OTH) AF: 0.00197 AC: 4 AN: 2030

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

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: rs55953250; hg19: chr2-216226584; COSMIC: COSV60559284; COSMIC: COSV60559284;