21-45490827-T-A

Position:

• chr21-45490827-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):​c.2032-9T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,549,926 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0300

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-45490827-T-A is Benign according to our data. Variant chr21-45490827-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 446008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2032-9T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2572-9T>A		splice_polypyrimidine_tract_variant, intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.3277-9T>A		splice_polypyrimidine_tract_variant, intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2032-9T>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2572-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000347665
COL18A1	ENST00000342220.9	c.73-9T>A		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000339118
COL18A1	ENST00000359759.8	c.3277-9T>A		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 530 AN: 152006 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000721 AC: 111 AN: 153994 Hom.: 0 AF XY: 0.000551 AC XY: 45 AN XY: 81694

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000851

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000922

GnomAD4 exome AF: 0.000384 AC: 537 AN: 1397802 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 232 AN XY: 689424

Gnomad4 AFR exome AF: 0.0133

Gnomad4 AMR exome AF: 0.00118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.000931

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152124 Hom.: 3 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74366

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00413

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2017	- -

Knobloch syndrome 1;C5394374:Glaucoma, primary closed-angle Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144913625; hg19: chr21-46910741;