rs9979845

Variant names:

• chr21-45480033-G-A
• rs9979845
• NM_001379500.1:c.1312-37G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45480033-G-A
• chr21-45480033-G-C
• chr21-45480033-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.1312-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,610,918 control chromosomes in the GnomAD database, including 41,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2993 hom., cov: 31)
  • Exomes 𝑓: 0.23 (38149 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.578
• Publications: 14 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 21-45480033-G-A is Benign according to our data. Variant chr21-45480033-G-A is described in ClinVar as Benign. ClinVar VariationId is 261890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.1312-37G>A		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.2557-37G>A		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.1852-37G>A		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1312-37G>A		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.1852-37G>A		intron	N/A	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.2557-37G>A		intron	N/A	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29336 AN: 151652 Hom.: 2993 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.209 AC: 51649 AN: 247158 AF XY: 0.210

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.226 AC: 330462 AN: 1459150 Hom.: 38149 Cov.: 33 AF XY: 0.226 AC XY: 163878 AN XY: 726084

African (AFR) AF: 0.110 AC: 3682 AN: 33386

American (AMR) AF: 0.221 AC: 9903 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6945 AN: 26116

East Asian (EAS) AF: 0.123 AC: 4866 AN: 39682

South Asian (SAS) AF: 0.182 AC: 15687 AN: 86192

European-Finnish (FIN) AF: 0.203 AC: 10799 AN: 53274

Middle Eastern (MID) AF: 0.250 AC: 1442 AN: 5760

European-Non Finnish (NFE) AF: 0.238 AC: 264191 AN: 1109728

Other (OTH) AF: 0.215 AC: 12947 AN: 60294

GnomAD4 genome AF: 0.193 AC: 29339 AN: 151768 Hom.: 2993 Cov.: 31 AF XY: 0.194 AC XY: 14370 AN XY: 74178

African (AFR) AF: 0.115 AC: 4771 AN: 41394

American (AMR) AF: 0.224 AC: 3425 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 890 AN: 3466

East Asian (EAS) AF: 0.139 AC: 715 AN: 5132

South Asian (SAS) AF: 0.183 AC: 878 AN: 4810

European-Finnish (FIN) AF: 0.208 AC: 2191 AN: 10558

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15853 AN: 67824

Other (OTH) AF: 0.214 AC: 453 AN: 2112

Alfa AF: 0.155 Hom.: 420

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	Knobloch syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	6.4
DANN	Benign	0.37
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9979845; hg19: chr21-46899947; COSMIC: COSV62702155; COSMIC: COSV62702155;