4-108863325-TCC-CCT

Variant names:

• chr4-108863325-TCC-CCT
• NM_198721.4:c.1144_1146delGGAinsAGG
• COL25A1 p.Gly382Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_198721.4(COL25A1):​c.1144_1146delGGAinsAGG​(p.Gly382Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL25A1 NM_198721.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• Publications: 0 publications found

Genes affected

COL25A1 (HGNC:18603): (collagen type XXV alpha 1 chain) This gene encodes a brain-specific membrane associated collagen. A product of proteolytic processing of the encoded protein, CLAC (collagenous Alzheimer amyloid plaque component), binds to amyloid beta-peptides found in Alzheimer amyloid plaques but CLAC inhibits rather than facilitates amyloid fibril elongation (PMID: 16300410). A study of over-expression of this collagen in mice, however, found changes in pathology and behavior suggesting that the encoded protein may promote amyloid plaque formation (PMID: 19548013). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

COL25A1 Gene-Disease associations (from GenCC):

• fibrosis of extraocular muscles, congenital, 5

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• ptosis, hereditary congenital, 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_198721.4 (COL25A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198721.4. 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
	COL25A1	NM_198721.4	MANE Select	c.1144_1146delGGAinsAGG	p.Gly382Arg	missense	N/A	NP_942014.1	Q9BXS0-1
	COL25A1	NM_001256074.3		c.1132_1134delGGAinsAGG	p.Gly378Arg	missense	N/A	NP_001243003.1	A8MWQ5
	COL25A1	NM_032518.4		c.1144_1146delGGAinsAGG	p.Gly382Arg	missense	N/A	NP_115907.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	ENST00000399132.6	TSL:5 MANE Select	c.1144_1146delGGAinsAGG	p.Gly382Arg	missense	N/A	ENSP00000382083.1	Q9BXS0-1
	COL25A1	ENST00000642955.1		c.1144_1146delGGAinsAGG	p.Gly382Arg	missense	N/A	ENSP00000495847.1	A0A2R8Y760
	COL25A1	ENST00000399127.5	TSL:5	c.1132_1134delGGAinsAGG	p.Gly378Arg	missense	N/A	ENSP00000382078.1	A8MWQ5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5

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: chr4-109784481;