21-45409447-T-C

Variant names:

• chr21-45409447-T-C
• rs11089001
• NM_001379500.1:c.106+3974T>C

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+3974T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,108 control chromosomes in the GnomAD database, including 3,054 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 0.17 (3054 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131
• Publications: 3 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-AS2 (HGNC:40155): (COL18A1 antisense RNA 2)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 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+3974T>C		intron	N/A	NP_001366429.1
	COL18A1-AS2	NR_052004.1		n.118+501A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+3974T>C		intron	N/A	ENSP00000498485.1
	COL18A1-AS2	ENST00000446475.1	TSL:4	n.118+501A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25124 AN: 151988 Hom.: 3023 Cov.: 33

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.155

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

GnomAD4 genome AF: 0.166 AC: 25204 AN: 152108 Hom.: 3054 Cov.: 33 AF XY: 0.171 AC XY: 12702 AN XY: 74390

African (AFR) AF: 0.272 AC: 11307 AN: 41496

American (AMR) AF: 0.235 AC: 3597 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.513 AC: 2630 AN: 5124

South Asian (SAS) AF: 0.112 AC: 541 AN: 4826

European-Finnish (FIN) AF: 0.109 AC: 1160 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5384 AN: 67960

Other (OTH) AF: 0.154 AC: 326 AN: 2112

Alfa AF: 0.0972 Hom.: 603

Bravo AF: 0.185

Asia WGS AF: 0.281 AC: 977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.13
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		2.0
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: rs11089001; hg19: chr21-46829362;