rs764710670

chr21-45486944-CCCCCCTGGG-Cchr21-45486944-C-CCCCCCTGGG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BP6

The NM_001379500.1(COL18A1):c.1800_1808del(p.Pro603_Pro605del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000531 in 1,486,532 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: COL18A1 NM_001379500.1 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001379500.1.
• BP6: Variant 21-45486944-CCCCCCTGGG-C is Benign according to our data. Variant chr21-45486944-CCCCCCTGGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447115.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr21-45486944-CCCCCCTGGG-C is described in Lovd as [Likely_benign]. Variant chr21-45486944-CCCCCCTGGG-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.1800_1808del	p.Pro603_Pro605del	inframe_deletion	16/42	ENST00000651438.1
COL18A1	NM_030582.4	c.2340_2348del	p.Pro783_Pro785del	inframe_deletion	15/41
COL18A1	NM_130444.3	c.3045_3053del	p.Pro1018_Pro1020del	inframe_deletion	15/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.1800_1808del	p.Pro603_Pro605del	inframe_deletion	16/42		NM_001379500.1
COL18A1	ENST00000355480.10	c.2340_2348del	p.Pro783_Pro785del	inframe_deletion	15/41	1
COL18A1	ENST00000359759.8	c.3045_3053del	p.Pro1018_Pro1020del	inframe_deletion	15/41	5		P1

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 147 AN: 151956 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00507

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000766 AC: 82 AN: 107000 Hom.: 1 AF XY: 0.000735 AC XY: 43 AN XY: 58514

Gnomad AFR exome AF: 0.00186

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00615

Gnomad SAS exome AF: 0.000130

Gnomad FIN exome AF: 0.000331

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000480 AC: 641 AN: 1334458 Hom.: 4 AF XY: 0.000468 AC XY: 307 AN XY: 656280

Gnomad4 AFR exome AF: 0.00228

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.0000927

Gnomad4 EAS exome AF: 0.00714

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.000428

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000508

GnomAD4 genome AF: 0.000980 AC: 149 AN: 152074 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74352

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00488

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.00114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 17, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs764710670; hg19: chr21-46906858;