rs76547444

chr21-45477753-G-A

Variant summary

Our verdict is Benign. Variant got -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. 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:3
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.1009G>A	p.Gly337Ser	missense_variant	8/42	ENST00000651438.1
COL18A1	NM_130444.3	c.2254G>A	p.Gly752Ser	missense_variant	7/41
COL18A1	NM_030582.4	c.1549G>A	p.Gly517Ser	missense_variant	7/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.1009G>A	p.Gly337Ser	missense_variant	8/42		NM_001379500.1
COL18A1	ENST00000355480.10	c.1549G>A	p.Gly517Ser	missense_variant	7/41	1
COL18A1	ENST00000359759.8	c.2254G>A	p.Gly752Ser	missense_variant	7/41	5		P1

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

GnomAD3 exomes AF: 0.00222 AC: 315 AN: 141732 Hom.: 4 AF XY: 0.00181 AC XY: 138 AN XY: 76328

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 SAS exome AF: 0.0000889

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

Gnomad4 AFR exome AF: 0.0388

Gnomad4 AMR exome AF: 0.00261

Gnomad4 ASJ exome AF: 0.0000403

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000428

Gnomad4 OTH exome AF: 0.00264

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

Gnomad4 AFR AF: 0.0356

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00200 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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.58	P;P;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs76547444; hg19: chr21-46897667;