rs776751637

Variant names:

• chr21-45505220-CCCTCCCGGC-CCCT
• NM_001379500.1:c.2962_2967delGGCCCC

Your query was ambiguous. Multiple possible variants found:

• chr21-45505223-TCCCGGCCCC-T
• chr21-45505223-TCCCGGCCCC-TCCCGGCCCCCCCGGCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_001379500.1(COL18A1):​c.2962_2967delGGCCCC​(p.Gly988_Pro989del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G988G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL18A1 NM_001379500.1 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001379500.1.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.2962_2967delGGCCCC	p.Gly988_Pro989del	conservative_inframe_deletion	Exon 35 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4207_4212delGGCCCC	p.Gly1403_Pro1404del	conservative_inframe_deletion	Exon 34 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3502_3507delGGCCCC	p.Gly1168_Pro1169del	conservative_inframe_deletion	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.2962_2967delGGCCCC	p.Gly988_Pro989del	conservative_inframe_deletion	Exon 35 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3502_3507delGGCCCC	p.Gly1168_Pro1169del	conservative_inframe_deletion	Exon 34 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-6617_1294-6612delGCCGGG		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-46925134;