NM_001379500.1:c.106+12321A>G

Variant names:

• chr21-45417794-A-G
• rs2838913
• NM_001379500.1:c.106+12321A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.106+12321A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,158 control chromosomes in the GnomAD database, including 37,989 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37989 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870
• Publications: 7 publications found

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.106+12321A>G		intron	N/A	NP_001366429.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+12321A>G		intron	N/A	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107163 AN: 152040 Hom.: 37960 Cov.: 33

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.715

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.705 AC: 107246 AN: 152158 Hom.: 37989 Cov.: 33 AF XY: 0.712 AC XY: 52984 AN XY: 74374

African (AFR) AF: 0.656 AC: 27239 AN: 41522

American (AMR) AF: 0.733 AC: 11214 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2555 AN: 3470

East Asian (EAS) AF: 0.860 AC: 4437 AN: 5160

South Asian (SAS) AF: 0.743 AC: 3577 AN: 4814

European-Finnish (FIN) AF: 0.771 AC: 8164 AN: 10590

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.701 AC: 47628 AN: 67982

Other (OTH) AF: 0.711 AC: 1502 AN: 2112

Alfa AF: 0.705 Hom.: 52056

Bravo AF: 0.699

Asia WGS AF: 0.777 AC: 2701 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.30
DANN	Benign	0.48
PhyloP100		-0.087
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2838913; hg19: chr21-46837709; COSMIC: COSV67268475; COSMIC: COSV67268475;