21-45512704-G-C

Variant names:

• chr21-45512704-G-C
• rs17004785
• NM_001379500.1:c.*306G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.*306G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 455,960 control chromosomes in the GnomAD database, including 2,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1015 hom., cov: 34)
  • Exomes 𝑓: 0.10 (1798 hom.)
• Consequence: COL18A1 NM_001379500.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.238
• Publications: 20 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 21-45512704-G-C is Benign according to our data. Variant chr21-45512704-G-C is described in ClinVar as Benign. ClinVar VariationId is 340282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.*306G>C		3_prime_UTR	Exon 42 of 42	NP_001366429.1
	SLC19A1	NM_194255.4	MANE Select	c.*2954C>G		3_prime_UTR	Exon 6 of 6	NP_919231.1
	COL18A1	NM_130444.3		c.*306G>C		3_prime_UTR	Exon 41 of 41	NP_569711.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.*306G>C		3_prime_UTR	Exon 42 of 42	ENSP00000498485.1
	SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.*2954C>G		3_prime_UTR	Exon 6 of 6	ENSP00000308895.4
	COL18A1	ENST00000355480.10	TSL:1	c.*306G>C		3_prime_UTR	Exon 41 of 41	ENSP00000347665.5

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17272 AN: 152102 Hom.: 1013 Cov.: 34

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.115

GnomAD4 exome AF: 0.103 AC: 31421 AN: 303740 Hom.: 1798 Cov.: 0 AF XY: 0.101 AC XY: 16110 AN XY: 160124

African (AFR) AF: 0.114 AC: 1045 AN: 9140

American (AMR) AF: 0.178 AC: 2198 AN: 12356

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 973 AN: 9224

East Asian (EAS) AF: 0.0495 AC: 877 AN: 17702

South Asian (SAS) AF: 0.0677 AC: 2715 AN: 40126

European-Finnish (FIN) AF: 0.122 AC: 2054 AN: 16824

Middle Eastern (MID) AF: 0.0972 AC: 123 AN: 1266

European-Non Finnish (NFE) AF: 0.109 AC: 19559 AN: 179872

Other (OTH) AF: 0.109 AC: 1877 AN: 17230

GnomAD4 genome AF: 0.114 AC: 17279 AN: 152220 Hom.: 1015 Cov.: 34 AF XY: 0.113 AC XY: 8396 AN XY: 74422

African (AFR) AF: 0.117 AC: 4850 AN: 41532

American (AMR) AF: 0.164 AC: 2511 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3472

East Asian (EAS) AF: 0.0554 AC: 287 AN: 5182

South Asian (SAS) AF: 0.0613 AC: 296 AN: 4828

European-Finnish (FIN) AF: 0.117 AC: 1241 AN: 10594

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7365 AN: 68002

Other (OTH) AF: 0.114 AC: 241 AN: 2112

Alfa AF: 0.0475 Hom.: 57

Bravo AF: 0.117

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Knobloch syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		0.24
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: rs17004785; hg19: chr21-46932618;