rs7279077

Positions:

• chr21-45468065-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001379500.1(COL18A1):​c.107-177A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,182 control chromosomes in the GnomAD database, including 5,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (5068 hom., cov: 34)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.87

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 21-45468065-A-T is Benign according to our data. Variant chr21-45468065-A-T is described in ClinVar as [Benign]. Clinvar id is 1283503.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.107-177A>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.1352-177A>T		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.647-177A>T		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.107-177A>T		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.647-177A>T		intron_variant		1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.1352-177A>T		intron_variant		5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33407 AN: 152064 Hom.: 5058 Cov.: 34

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.199

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33465 AN: 152182 Hom.: 5068 Cov.: 34 AF XY: 0.220 AC XY: 16342 AN XY: 74418

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.238

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.198

Alfa AF: 0.178 Hom.: 420

Bravo AF: 0.230

Asia WGS AF: 0.193 AC: 674 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.94
DANN	Benign	0.54

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: rs7279077; hg19: chr21-46887979;