21-45505223-TCCCGGCCCC-TCCCGGCCCCCCCGGCCCC

Variant names:

• chr21-45505223-T-TCCCGGCCCC
• rs776751637
• NM_001379500.1:c.2961_2969dupCGGCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM4 BP6_Moderate

The NM_001379500.1(COL18A1):​c.2961_2969dupCGGCCCCCC​(p.Pro990_Gly991insGlyProPro) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000038 in 1,580,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P990P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.76
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001379500.1.
• BP6: Variant 21-45505223-T-TCCCGGCCCC is Benign according to our data. Variant chr21-45505223-T-TCCCGGCCCC is described in ClinVar as Benign. ClinVar VariationId is 402552.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2961_2969dupCGGCCCCCC	p.Pro990_Gly991insGlyProPro	disruptive_inframe_insertion	Exon 35 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4206_4214dupCGGCCCCCC	p.Pro1405_Gly1406insGlyProPro	disruptive_inframe_insertion	Exon 34 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3501_3509dupCGGCCCCCC	p.Pro1170_Gly1171insGlyProPro	disruptive_inframe_insertion	Exon 34 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2961_2969dupCGGCCCCCC	p.Pro990_Gly991insGlyProPro	disruptive_inframe_insertion	Exon 35 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3501_3509dupCGGCCCCCC	p.Pro1170_Gly1171insGlyProPro	disruptive_inframe_insertion	Exon 34 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-6620_1294-6612dupGGGGCCGGG		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148324 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1432356 Hom.: 0 Cov.: 32 AF XY: 0.00000421 AC XY: 3 AN XY: 712750

African (AFR) AF: 0.0000330 AC: 1 AN: 30310

American (AMR) AF: 0.0000231 AC: 1 AN: 43214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094194

Other (OTH) AF: 0.00 AC: 0 AN: 59060

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148324 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 1 AN XY: 72462

African (AFR) AF: 0.0000519 AC: 2 AN: 38560

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67626

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=64/36	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs776751637; hg19: chr21-46925137;