NM_001379500.1:c.3681C>T

Variant names:

• chr21-45510249-C-T
• rs2838952
• NM_001379500.1:c.3681C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):​c.3681C>T​(p.Ile1227Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,604,708 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (88 hom., cov: 34)
  • Exomes 𝑓: 0.032 (1086 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.73
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.086).
• BP6: Variant 21-45510249-C-T is Benign according to our data. Variant chr21-45510249-C-T is described in ClinVar as Benign. ClinVar VariationId is 522315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.3681C>T	p.Ile1227Ile	synonymous	Exon 40 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.4926C>T	p.Ile1642Ile	synonymous	Exon 39 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4221C>T	p.Ile1407Ile	synonymous	Exon 39 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3681C>T	p.Ile1227Ile	synonymous	Exon 40 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.4221C>T	p.Ile1407Ile	synonymous	Exon 39 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-11637G>A		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 4059 AN: 152202 Hom.: 86 Cov.: 34

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0314

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0403 AC: 9068 AN: 225060 AF XY: 0.0353

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.00406

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0324 AC: 47108 AN: 1452388 Hom.: 1086 Cov.: 33 AF XY: 0.0314 AC XY: 22682 AN XY: 722064

African (AFR) AF: 0.00521 AC: 173 AN: 33212

American (AMR) AF: 0.130 AC: 5665 AN: 43726

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 130 AN: 25950

East Asian (EAS) AF: 0.000205 AC: 8 AN: 39104

South Asian (SAS) AF: 0.0202 AC: 1714 AN: 84838

European-Finnish (FIN) AF: 0.0275 AC: 1414 AN: 51452

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5758

European-Non Finnish (NFE) AF: 0.0329 AC: 36442 AN: 1108364

Other (OTH) AF: 0.0248 AC: 1485 AN: 59984

GnomAD4 genome AF: 0.0267 AC: 4071 AN: 152320 Hom.: 88 Cov.: 34 AF XY: 0.0271 AC XY: 2015 AN XY: 74490

African (AFR) AF: 0.00765 AC: 318 AN: 41574

American (AMR) AF: 0.0742 AC: 1135 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4830

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0314 AC: 2135 AN: 68012

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0308 Hom.: 244

Bravo AF: 0.0317

Asia WGS AF: 0.0100 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Knobloch syndrome Benign:2

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.6
DANN	Benign	0.94
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=95/5	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: rs2838952; hg19: chr21-46930163; COSMIC: COSV108133515; COSMIC: COSV108133515;