rs8126757

Variant names:

• chr21-45428367-A-G
• rs8126757
• NM_001379500.1:c.106+22894A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-45428367-A-G
• chr21-45428367-A-T

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+22894A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,104 control chromosomes in the GnomAD database, including 8,117 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 0.29 (8117 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265
• Publications: 9 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+22894A>G		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+22894A>G		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43713 AN: 151986 Hom.: 8083 Cov.: 33

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.288 AC: 43808 AN: 152104 Hom.: 8117 Cov.: 33 AF XY: 0.295 AC XY: 21934 AN XY: 74376

African (AFR) AF: 0.507 AC: 21035 AN: 41476

American (AMR) AF: 0.300 AC: 4583 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 739 AN: 3468

East Asian (EAS) AF: 0.504 AC: 2611 AN: 5180

South Asian (SAS) AF: 0.252 AC: 1214 AN: 4814

European-Finnish (FIN) AF: 0.249 AC: 2641 AN: 10590

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10223 AN: 67980

Other (OTH) AF: 0.265 AC: 560 AN: 2110

Alfa AF: 0.188 Hom.: 5828

Bravo AF: 0.299

Asia WGS AF: 0.358 AC: 1247 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.1
DANN	Benign	0.54
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs8126757; hg19: chr21-46848282;