NM_001379500.1:c.2577+37delC

Variant names:

• chr21-45496602-AC-A
• rs397867048
• NM_001379500.1:c.2577+37delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.2577+37delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18617 hom., cov: 0)
  • Exomes 𝑓: 0.43 (80652 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.56
• Publications: 2 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]

SLC19A1 Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• immunodeficiency 114, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• megaloblastic anemia, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 21-45496602-AC-A is Benign according to our data. Variant chr21-45496602-AC-A is described in ClinVar as Benign. ClinVar VariationId is 261902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2577+37delC		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3822+37delC		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3117+37delC		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2577+35delC		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3117+35delC		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000417954.5	TSL:1	c.763-224delG		intron	N/A	ENSP00000393988.1	H0Y4T2

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74077 AN: 151798 Hom.: 18591 Cov.: 0

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.488

GnomAD2 exomes AF: 0.448 AC: 109638 AN: 244798 AF XY: 0.447

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.405

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.393

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.432 AC: 357651 AN: 827050 Hom.: 80652 Cov.: 0 AF XY: 0.434 AC XY: 189206 AN XY: 436380

African (AFR) AF: 0.590 AC: 12519 AN: 21208

American (AMR) AF: 0.409 AC: 17970 AN: 43964

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 9964 AN: 22270

East Asian (EAS) AF: 0.320 AC: 11825 AN: 36940

South Asian (SAS) AF: 0.416 AC: 30721 AN: 73780

European-Finnish (FIN) AF: 0.511 AC: 26435 AN: 51728

Middle Eastern (MID) AF: 0.517 AC: 2175 AN: 4204

European-Non Finnish (NFE) AF: 0.428 AC: 228442 AN: 533574

Other (OTH) AF: 0.447 AC: 17600 AN: 39382

GnomAD4 genome AF: 0.488 AC: 74142 AN: 151920 Hom.: 18617 Cov.: 0 AF XY: 0.491 AC XY: 36488 AN XY: 74266

African (AFR) AF: 0.589 AC: 24385 AN: 41434

American (AMR) AF: 0.433 AC: 6622 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1603 AN: 3464

East Asian (EAS) AF: 0.377 AC: 1933 AN: 5126

South Asian (SAS) AF: 0.416 AC: 2010 AN: 4826

European-Finnish (FIN) AF: 0.538 AC: 5684 AN: 10560

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30334 AN: 67918

Other (OTH) AF: 0.487 AC: 1026 AN: 2108

Alfa AF: 0.465 Hom.: 3012

Bravo AF: 0.486

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	Knobloch syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.6
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: rs397867048; hg19: chr21-46916516; COSMIC: COSV107421621; COSMIC: COSV107421621;