21-45485910-C-T

Position:

• chr21-45485910-C-T

Variant summary

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

The NM_001379500.1(COL18A1):​c.1702-951C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0475 in 152,312 control chromosomes in the GnomAD database, including 446 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 0.048 (446 hom., cov: 32)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.993

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1702-951C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.2947-951C>T		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2242-951C>T		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1702-951C>T		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2242-951C>T		intron_variant		1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.2947-951C>T		intron_variant		5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7228 AN: 152194 Hom.: 445 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0929

Gnomad SAS AF: 0.0577

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.0340

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

GnomAD4 genome AF: 0.0475 AC: 7239 AN: 152312 Hom.: 446 Cov.: 32 AF XY: 0.0476 AC XY: 3546 AN XY: 74480

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0929

Gnomad4 SAS AF: 0.0571

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00497

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.00788 Hom.: 9

Bravo AF: 0.0521

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.16
DANN	Benign	0.66
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.9

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: rs2838944; hg19: chr21-46905824;