rs113268527

Variant names:

• chr21-45509458-G-A
• rs113268527
• NM_001379500.1:c.3352G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_130444.3(COL18A1):​c.4597G>A​(p.Ala1533Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,533,408 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1533A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 33)
  • Exomes 𝑓: 0.011 (114 hom.)
• Consequence: COL18A1 NM_130444.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.715
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067158937).
• BP6: Variant 21-45509458-G-A is Benign according to our data. Variant chr21-45509458-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.3352G>A	p.Ala1118Thr	missense	Exon 39 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.4597G>A	p.Ala1533Thr	missense	Exon 38 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3892G>A	p.Ala1298Thr	missense	Exon 38 of 41	NP_085059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3352G>A	p.Ala1118Thr	missense	Exon 39 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.3892G>A	p.Ala1298Thr	missense	Exon 38 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-10846C>T		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1044 AN: 152058 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00659 AC: 902 AN: 136796 AF XY: 0.00692

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.0110 AC: 15131 AN: 1381234 Hom.: 114 Cov.: 32 AF XY: 0.0107 AC XY: 7303 AN XY: 681828

African (AFR) AF: 0.00162 AC: 51 AN: 31548

American (AMR) AF: 0.00284 AC: 103 AN: 36310

Ashkenazi Jewish (ASJ) AF: 0.00120 AC: 30 AN: 25016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35870

South Asian (SAS) AF: 0.00130 AC: 103 AN: 79244

European-Finnish (FIN) AF: 0.00472 AC: 176 AN: 37288

Middle Eastern (MID) AF: 0.00206 AC: 10 AN: 4856

European-Non Finnish (NFE) AF: 0.0133 AC: 14314 AN: 1073608

Other (OTH) AF: 0.00598 AC: 344 AN: 57494

GnomAD4 genome AF: 0.00686 AC: 1044 AN: 152174 Hom.: 6 Cov.: 33 AF XY: 0.00629 AC XY: 468 AN XY: 74392

African (AFR) AF: 0.00181 AC: 75 AN: 41520

American (AMR) AF: 0.00320 AC: 49 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 67966

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00834 Hom.: 3

Bravo AF: 0.00676

ESP6500AA AF: 0.000634 AC: 2

ESP6500EA AF: 0.00793 AC: 56

ExAC AF: 0.00439 AC: 467

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.71
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.011	D
Sift4G	Benign	0.10	T
Polyphen		0.57	P
Vest4		0.31
MVP		0.81
MPC		0.23
ClinPred		0.016	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.092
gMVP		0.47
Mutation Taster		=93/7	polymorphism

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: rs113268527; hg19: chr21-46929372; COSMIC: COSV60589762; COSMIC: COSV60589762;