chr21-45493697-T-C

Position:

• chr21-45493697-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.2352+122T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 757,172 control chromosomes in the GnomAD database, including 12,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2243 hom., cov: 34)
  • Exomes 𝑓: 0.18 (10288 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21

Genes affected

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

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]

COL18A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 21-45493697-T-C is Benign according to our data. Variant chr21-45493697-T-C is described in ClinVar as [Benign]. Clinvar id is 1235277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2352+122T>C		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3597+122T>C		intron_variant			NP_569711.2
COL18A1	NM_030582.4	c.2892+122T>C		intron_variant			NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2352+122T>C		intron_variant			NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25566 AN: 152064 Hom.: 2244 Cov.: 34

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.195

GnomAD4 exome AF: 0.180 AC: 109102 AN: 604990 Hom.: 10288 Cov.: 8 AF XY: 0.180 AC XY: 57032 AN XY: 317530

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.168 AC: 25561 AN: 152182 Hom.: 2243 Cov.: 34 AF XY: 0.168 AC XY: 12519 AN XY: 74422

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.194

Alfa AF: 0.177 Hom.: 269

Bravo AF: 0.169

Asia WGS AF: 0.155 AC: 539 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73228774; hg19: chr21-46913611;