chr21-45476467-G-T

Variant names:

• chr21-45476467-G-T
• rs17338853
• NM_001379500.1:c.915G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):​c.915G>T​(p.Val305Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,608,854 control chromosomes in the GnomAD database, including 1,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (85 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1135 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0710
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-45476467-G-T is Benign according to our data. Variant chr21-45476467-G-T is described in ClinVar as Benign. ClinVar VariationId is 261888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0278 (4236/152248) while in subpopulation NFE AF = 0.0419 (2849/68014). AF 95% confidence interval is 0.0406. There are 85 homozygotes in GnomAd4. There are 1993 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AD,AR gene

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.915G>T	p.Val305Val	synonymous	Exon 6 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.2160G>T	p.Val720Val	synonymous	Exon 5 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.1455G>T	p.Val485Val	synonymous	Exon 5 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.915G>T	p.Val305Val	synonymous	Exon 6 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.1455G>T	p.Val485Val	synonymous	Exon 5 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.2160G>T	p.Val720Val	synonymous	Exon 5 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4240 AN: 152130 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0322 AC: 7556 AN: 234672 AF XY: 0.0330

Gnomad AFR exome AF: 0.00722

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.00716

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0428

Gnomad OTH exome AF: 0.0368

GnomAD4 exome AF: 0.0378 AC: 55034 AN: 1456606 Hom.: 1135 Cov.: 33 AF XY: 0.0379 AC XY: 27464 AN XY: 724168

African (AFR) AF: 0.00638 AC: 213 AN: 33390

American (AMR) AF: 0.0318 AC: 1392 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 490 AN: 25966

East Asian (EAS) AF: 0.00968 AC: 382 AN: 39476

South Asian (SAS) AF: 0.0357 AC: 3056 AN: 85494

European-Finnish (FIN) AF: 0.0182 AC: 966 AN: 53008

Middle Eastern (MID) AF: 0.0406 AC: 234 AN: 5758

European-Non Finnish (NFE) AF: 0.0416 AC: 46113 AN: 1109568

Other (OTH) AF: 0.0364 AC: 2188 AN: 60160

GnomAD4 genome AF: 0.0278 AC: 4236 AN: 152248 Hom.: 85 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74450

African (AFR) AF: 0.00761 AC: 316 AN: 41532

American (AMR) AF: 0.0344 AC: 526 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5182

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4834

European-Finnish (FIN) AF: 0.0140 AC: 148 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0419 AC: 2849 AN: 68014

Other (OTH) AF: 0.0288 AC: 61 AN: 2116

Alfa AF: 0.0370 Hom.: 180

Bravo AF: 0.0288

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Knobloch syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.38
DANN	Benign	0.50
PhyloP100		0.071
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17338853; hg19: chr21-46896381;