rs73370840

Variant names:

• chr21-45497121-C-T
• rs73370840
• NM_001379500.1:c.2620+29C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130444.3(COL18A1):​c.3865+29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,458,396 control chromosomes in the GnomAD database, including 17,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2071 hom., cov: 33)
  • Exomes 𝑓: 0.15 (15574 hom.)
• Consequence: COL18A1 NM_130444.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.52
• Publications: 8 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-45497121-C-T is Benign according to our data. Variant chr21-45497121-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2620+29C>T		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.3865+29C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3160+29C>T		intron	N/A	NP_085059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2620+29C>T		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.3160+29C>T		intron	N/A	ENSP00000347665.5
	SLC19A1	ENST00000417954.5	TSL:1	c.763-742G>A		intron	N/A	ENSP00000393988.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24001 AN: 152008 Hom.: 2069 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.142 AC: 33780 AN: 237882 AF XY: 0.146

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.0807

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0183

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.149 AC: 195064 AN: 1306270 Hom.: 15574 Cov.: 20 AF XY: 0.150 AC XY: 98852 AN XY: 657868

African (AFR) AF: 0.162 AC: 4996 AN: 30746

American (AMR) AF: 0.0842 AC: 3751 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2845 AN: 25314

East Asian (EAS) AF: 0.0146 AC: 571 AN: 39164

South Asian (SAS) AF: 0.154 AC: 12821 AN: 83446

European-Finnish (FIN) AF: 0.214 AC: 8658 AN: 40406

Middle Eastern (MID) AF: 0.138 AC: 740 AN: 5376

European-Non Finnish (NFE) AF: 0.156 AC: 152704 AN: 981552

Other (OTH) AF: 0.143 AC: 7978 AN: 55730

GnomAD4 genome AF: 0.158 AC: 24025 AN: 152126 Hom.: 2071 Cov.: 33 AF XY: 0.159 AC XY: 11814 AN XY: 74368

African (AFR) AF: 0.165 AC: 6840 AN: 41500

American (AMR) AF: 0.112 AC: 1709 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 406 AN: 3468

East Asian (EAS) AF: 0.0161 AC: 83 AN: 5166

South Asian (SAS) AF: 0.151 AC: 728 AN: 4826

European-Finnish (FIN) AF: 0.245 AC: 2591 AN: 10582

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11230 AN: 67976

Other (OTH) AF: 0.131 AC: 275 AN: 2106

Alfa AF: 0.156 Hom.: 366

Bravo AF: 0.148

Asia WGS AF: 0.0860 AC: 300 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.56
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73370840; hg19: chr21-46917035;