2-215361861-GTTTTT-GTTTTTTT

Variant names:

• chr2-215361861-G-GTT
• rs55953250
• NM_212482.4:c.7362+106_7362+107dupAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_212482.4(FN1):​c.7362+106_7362+107dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,131,334 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-215361861-G-GTT is Benign according to our data. Variant chr2-215361861-G-GTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1201817.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00529 (777/146888) while in subpopulation AFR AF = 0.0184 (738/40210). AF 95% confidence interval is 0.0173. There are 6 homozygotes in GnomAd4. There are 372 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 777 AD gene.

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.7362+106_7362+107dupAA		intron	N/A	NP_997647.2	P02751-15
	FN1	NM_001306129.2		c.7269+106_7269+107dupAA		intron	N/A	NP_001293058.2	P02751-7
	FN1	NM_001365517.2		c.7092+106_7092+107dupAA		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.7362+107_7362+108insAA		intron	N/A	ENSP00000346839.4	P02751-15
	FN1	ENST00000323926.10	TSL:1	c.7269+107_7269+108insAA		intron	N/A	ENSP00000323534.6	P02751-7
	FN1	ENST00000336916.8	TSL:1	c.6996+107_6996+108insAA		intron	N/A	ENSP00000338200.4	P02751-3

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 778 AN: 146804 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000604

Gnomad OTH AF: 0.00347

GnomAD4 exome AF: 0.000631 AC: 621 AN: 984446 Hom.: 0 Cov.: 18 AF XY: 0.000578 AC XY: 281 AN XY: 486330

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

African (AFR) AF: 0.0188 AC: 413 AN: 21966

American (AMR) AF: 0.00171 AC: 38 AN: 22224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17540

East Asian (EAS) AF: 0.000501 AC: 13 AN: 25942

South Asian (SAS) AF: 0.000128 AC: 7 AN: 54746

European-Finnish (FIN) AF: 0.0000296 AC: 1 AN: 33810

Middle Eastern (MID) AF: 0.000351 AC: 1 AN: 2852

European-Non Finnish (NFE) AF: 0.000112 AC: 86 AN: 764634

Other (OTH) AF: 0.00152 AC: 62 AN: 40732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00529 AC: 777 AN: 146888 Hom.: 6 Cov.: 32 AF XY: 0.00520 AC XY: 372 AN XY: 71564

African (AFR) AF: 0.0184 AC: 738 AN: 40210

American (AMR) AF: 0.00184 AC: 27 AN: 14666

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

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5038

South Asian (SAS) AF: 0.00 AC: 0 AN: 4646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000604 AC: 4 AN: 66248

Other (OTH) AF: 0.00344 AC: 7 AN: 2034

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55953250; hg19: chr2-216226584;