chr21-45473910-C-T

Position:

• chr21-45473910-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):​c.667C>T​(p.Leu223Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000834 in 1,604,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.589

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 21-45473910-C-T is Benign according to our data. Variant chr21-45473910-C-T is described in ClinVar as [Benign]. Clinvar id is 447133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45473910-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.589 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000475 (689/1451796) while in subpopulation AFR AF= 0.0166 (552/33230). AF 95% confidence interval is 0.0155. There are 2 homozygotes in gnomad4_exome. There are 301 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.667C>T	p.Leu223Leu	synonymous_variant	4/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.1912C>T	p.Leu638Leu	synonymous_variant	3/41		NP_569711.2
COL18A1	NM_030582.4	c.1207C>T	p.Leu403Leu	synonymous_variant	3/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.667C>T	p.Leu223Leu	synonymous_variant	4/42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.1207C>T	p.Leu403Leu	synonymous_variant	3/41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.1912C>T	p.Leu638Leu	synonymous_variant	3/41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 152180 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000952 AC: 218 AN: 229012 Hom.: 0 AF XY: 0.000659 AC XY: 82 AN XY: 124494

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000706

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.000709

GnomAD4 exome AF: 0.000475 AC: 689 AN: 1451796 Hom.: 2 Cov.: 31 AF XY: 0.000417 AC XY: 301 AN XY: 721182

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000619

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000593

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000298

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152298 Hom.: 6 Cov.: 32 AF XY: 0.00444 AC XY: 331 AN XY: 74466

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00495

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.7
DANN	Benign	0.43

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: rs60162212; hg19: chr21-46893824;