rs76547444

Variant names:

• chr21-45477753-G-A
• rs76547444
• NM_001379500.1:c.1009G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):​c.1009G>A​(p.Gly337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,537,764 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.02
• Publications: 4 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 21-45477753-G-A is Benign according to our data. Variant chr21-45477753-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 340210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1601/152326) while in subpopulation AFR AF = 0.0356 (1480/41570). AF 95% confidence interval is 0.0341. There are 32 homozygotes in GnomAd4. There are 778 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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.1009G>A	p.Gly337Ser	missense	Exon 8 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.2254G>A	p.Gly752Ser	missense	Exon 7 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.1549G>A	p.Gly517Ser	missense	Exon 7 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.1009G>A	p.Gly337Ser	missense	Exon 8 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.1549G>A	p.Gly517Ser	missense	Exon 7 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.2254G>A	p.Gly752Ser	missense	Exon 7 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1597 AN: 152208 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00222 AC: 315 AN: 141732 AF XY: 0.00181

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000917

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00110 AC: 1529 AN: 1385438 Hom.: 27 Cov.: 32 AF XY: 0.000942 AC XY: 643 AN XY: 682414

African (AFR) AF: 0.0388 AC: 1217 AN: 31394

American (AMR) AF: 0.00261 AC: 92 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.0000403 AC: 1 AN: 24844

East Asian (EAS) AF: 0.00 AC: 0 AN: 35566

South Asian (SAS) AF: 0.000127 AC: 10 AN: 78938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42410

Middle Eastern (MID) AF: 0.00197 AC: 11 AN: 5576

European-Non Finnish (NFE) AF: 0.0000428 AC: 46 AN: 1073898

Other (OTH) AF: 0.00264 AC: 152 AN: 57506

GnomAD4 genome AF: 0.0105 AC: 1601 AN: 152326 Hom.: 32 Cov.: 33 AF XY: 0.0104 AC XY: 778 AN XY: 74476

African (AFR) AF: 0.0356 AC: 1480 AN: 41570

American (AMR) AF: 0.00595 AC: 91 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.0122

ESP6500AA AF: 0.0290 AC: 98

ESP6500EA AF: 0.000268 AC: 2

ExAC AF: 0.00147 AC: 125

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Knobloch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Uncertain	0.021	D
Sift4G	Benign	0.14	T
Polyphen		0.58	P
Vest4		0.087
MVP		0.59
MPC		0.067
ClinPred		0.021	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.74
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.61		Position offset: 2

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

Other links and lift over

dbSNP: rs76547444; hg19: chr21-46897667;