rs2838917

Positions:

• chr21-45419989-T-C
• chr21-45419989-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.106+14516T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 152,050 control chromosomes in the GnomAD database, including 29,837 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29830 hom., cov: 32)
  • Exomes 𝑓: 0.80 (7 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.313

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]

COL18A1-AS1 (HGNC:23132): (COL18A1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.106+14516T>C		intron_variant		ENST00000651438.1
COL18A1-AS1	NR_027498.1	n.2068A>G		non_coding_transcript_exon_variant	3/3
COL18A1-AS1	NR_028082.1	n.3152A>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+14516T>C		intron_variant			NM_001379500.1
COL18A1-AS1	ENST00000397787.5	n.3152A>G		non_coding_transcript_exon_variant	3/3	1
COL18A1-AS1	ENST00000485206.1	n.2068A>G		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93778 AN: 151910 Hom.: 29836 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.787

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.629

GnomAD4 exome AF: 0.800 AC: 16 AN: 20 Hom.: 7 Cov.: 0 AF XY: 0.750 AC XY: 12 AN XY: 16

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.833

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.617 AC: 93801 AN: 152030 Hom.: 29830 Cov.: 32 AF XY: 0.620 AC XY: 46061 AN XY: 74316

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.559

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.541

Gnomad4 SAS AF: 0.701

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.699

Gnomad4 OTH AF: 0.628

Alfa AF: 0.682 Hom.: 56614

Bravo AF: 0.594

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.28

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2838917; hg19: chr21-46839904; COSMIC: COSV67268477;