rs370656151

chr21-45505380-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001379500.1(COL18A1):c.3036G>A(p.Pro1012=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,585,962 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.49

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 21-45505380-G-A is Benign according to our data. Variant chr21-45505380-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45505380-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.49 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3036G>A	p.Pro1012=	synonymous_variant	36/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3036G>A	p.Pro1012=	synonymous_variant	36/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 334 AN: 151908 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00355

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00210 AC: 492 AN: 233744 Hom.: 3 AF XY: 0.00203 AC XY: 259 AN XY: 127838

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.000175

Gnomad SAS exome AF: 0.000506

Gnomad FIN exome AF: 0.000824

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00323 AC: 4637 AN: 1433936 Hom.: 11 Cov.: 28 AF XY: 0.00315 AC XY: 2252 AN XY: 714106

Gnomad4 AFR exome AF: 0.000484

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.000518

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.00220 AC: 334 AN: 152026 Hom.: 1 Cov.: 34 AF XY: 0.00195 AC XY: 145 AN XY: 74308

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00355

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 18, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

COL18A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Knobloch syndrome 1;C5394374:Glaucoma, primary closed-angle Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 31, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.015
Dann	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs370656151; hg19: chr21-46925294;