NM_001379500.1:c.3837G>A

Variant names:

• chr21-45512215-G-A
• rs113315760
• NM_001379500.1:c.3837G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001379500.1(COL18A1):​c.3837G>A​(p.Ser1279Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,612,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -8.40
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.147).
• BP6: Variant 21-45512215-G-A is Benign according to our data. Variant chr21-45512215-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 447130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.4 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.3837G>A	p.Ser1279Ser	synonymous	Exon 42 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.5082G>A	p.Ser1694Ser	synonymous	Exon 41 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4377G>A	p.Ser1459Ser	synonymous	Exon 41 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3837G>A	p.Ser1279Ser	synonymous	Exon 42 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.4377G>A	p.Ser1459Ser	synonymous	Exon 41 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1293+13602C>T		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000989 AC: 239 AN: 241570 AF XY: 0.000937

Gnomad AFR exome AF: 0.000544

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.000810

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00161 AC: 2350 AN: 1459782 Hom.: 3 Cov.: 32 AF XY: 0.00153 AC XY: 1109 AN XY: 726200

African (AFR) AF: 0.000299 AC: 10 AN: 33458

American (AMR) AF: 0.000717 AC: 32 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000920 AC: 24 AN: 26096

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39630

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86156

European-Finnish (FIN) AF: 0.000479 AC: 25 AN: 52168

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00197 AC: 2186 AN: 1111604

Other (OTH) AF: 0.00106 AC: 64 AN: 60262

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74496

African (AFR) AF: 0.000529 AC: 22 AN: 41580

American (AMR) AF: 0.00111 AC: 17 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00131

EpiCase AF: 0.00180

EpiControl AF: 0.00232

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.034
DANN	Benign	0.93
PhyloP100		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs113315760; hg19: chr21-46932129;