2-215361861-GT-G

Variant names:

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

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+107delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,084,532 control chromosomes in the GnomAD database, including 98 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (15 hom., cov: 32)
  • Exomes 𝑓: 0.027 (83 hom.)
• Consequence: FN1 NM_212482.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.478

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]

ACMG classification

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

• BP6: Variant 2-215361861-GT-G is Benign according to our data. Variant chr2-215361861-GT-G is described in ClinVar as [Likely_benign]. Clinvar id is 1191483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0159 (2341/146804) while in subpopulation AFR AF = 0.0242 (971/40206). AF 95% confidence interval is 0.0229. There are 15 homozygotes in GnomAd4. There are 1168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2341 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FN1	NM_212482.4	c.7362+107delA		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+107delA		intron_variant	Intron 45 of 45	1	NM_212482.4	ENSP00000346839.4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2340 AN: 146720 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000792

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00899

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0228

GnomAD4 exome AF: 0.0274 AC: 25716 AN: 937728 Hom.: 83 Cov.: 18 AF XY: 0.0276 AC XY: 12743 AN XY: 462262

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

African (AFR) AF: 0.0403 AC: 846 AN: 20998

American (AMR) AF: 0.0294 AC: 614 AN: 20852

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 738 AN: 16350

East Asian (EAS) AF: 0.0123 AC: 295 AN: 24038

South Asian (SAS) AF: 0.0254 AC: 1310 AN: 51660

European-Finnish (FIN) AF: 0.0266 AC: 848 AN: 31826

Middle Eastern (MID) AF: 0.0332 AC: 89 AN: 2684

European-Non Finnish (NFE) AF: 0.0271 AC: 19813 AN: 730892

Other (OTH) AF: 0.0303 AC: 1163 AN: 38428

⚠️ 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: 0.0159 AC: 2341 AN: 146804 Hom.: 15 Cov.: 32 AF XY: 0.0163 AC XY: 1168 AN XY: 71518

African (AFR) AF: 0.0242 AC: 971 AN: 40206

American (AMR) AF: 0.0156 AC: 229 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 79 AN: 3388

East Asian (EAS) AF: 0.000794 AC: 4 AN: 5036

South Asian (SAS) AF: 0.0129 AC: 60 AN: 4646

European-Finnish (FIN) AF: 0.00899 AC: 85 AN: 9450

Middle Eastern (MID) AF: 0.0208 AC: 6 AN: 288

European-Non Finnish (NFE) AF: 0.0124 AC: 818 AN: 66208

Other (OTH) AF: 0.0226 AC: 46 AN: 2032

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.0166

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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

Publications

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Other links and lift over

dbSNP: rs55953250; hg19: chr2-216226584; COSMIC: COSV60548211; COSMIC: COSV60548211;