rs113268527

Positions:

• chr21-45509458-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):​c.3352G>A​(p.Ala1118Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,533,408 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1118A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (114 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.715

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]

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067158937).
• BP6: Variant 21-45509458-G-A is Benign according to our data. Variant chr21-45509458-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45509458-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3352G>A	p.Ala1118Thr	missense_variant	39/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3352G>A	p.Ala1118Thr	missense_variant	39/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1044 AN: 152058 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00659 AC: 902 AN: 136796 Hom.: 8 AF XY: 0.00692 AC XY: 519 AN XY: 75044

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.0110 AC: 15131 AN: 1381234 Hom.: 114 Cov.: 32 AF XY: 0.0107 AC XY: 7303 AN XY: 681828

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.00472

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.00686 AC: 1044 AN: 152174 Hom.: 6 Cov.: 33 AF XY: 0.00629 AC XY: 468 AN XY: 74392

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00880 Hom.: 3

Bravo AF: 0.00676

ESP6500AA AF: 0.000634 AC: 2

ESP6500EA AF: 0.00793 AC: 56

ExAC AF: 0.00439 AC: 467

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COL18A1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	.;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	.;.;L;.
MutationTaster	Benign	0.90	N;N;N;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.011	D;D;D;T
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.57	P;P;P;.
Vest4		0.31
MVP		0.81
MPC		0.23
ClinPred		0.016	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.092
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs113268527; hg19: chr21-46929372; COSMIC: COSV60589762; COSMIC: COSV60589762;