rs78487064

chr21-45509639-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):c.3495+38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,093,156 control chromosomes in the GnomAD database, including 11,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2286 hom., cov: 34)
  • Exomes 𝑓: 0.14 (9351 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.459

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-45509639-C-G is Benign according to our data. Variant chr21-45509639-C-G is described in ClinVar as [Benign]. Clinvar id is 261911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3495+38C>G		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3495+38C>G		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25344 AN: 152042 Hom.: 2281 Cov.: 34

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.140 AC: 18146 AN: 129336 Hom.: 1347 AF XY: 0.137 AC XY: 9689 AN XY: 70894

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0560

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.138 AC: 130087 AN: 940996 Hom.: 9351 Cov.: 13 AF XY: 0.136 AC XY: 65636 AN XY: 481802

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0622

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.167 AC: 25381 AN: 152160 Hom.: 2286 Cov.: 34 AF XY: 0.164 AC XY: 12198 AN XY: 74378

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0597

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.166

Alfa AF: 0.151 Hom.: 279

Bravo AF: 0.174

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.8
Dann	Benign	0.57

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: rs78487064; hg19: chr21-46929553;