chr4-108818311-A-T

Variant names:

• chr4-108818311-A-T
• rs1963939
• NM_198721.4:c.1924-876T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198721.4(COL25A1):​c.1924-876T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics
• ptosis, hereditary congenital, 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

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.1924-876T>A		intron	N/A	NP_942014.1	Q9BXS0-1
	COL25A1	NR_045756.3		n.2121-876T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	ENST00000399132.6	TSL:5 MANE Select	c.1924-876T>A		intron	N/A	ENSP00000382083.1	Q9BXS0-1
	COL25A1	ENST00000642955.1		c.2050-876T>A		intron	N/A	ENSP00000495847.1	A0A2R8Y760
	COL25A1	ENST00000512961.5	TSL:5	c.46-876T>A		intron	N/A	ENSP00000426841.1	H0YAE1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.3
DANN	Benign	0.84
PhyloP100		0.016

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: rs1963939; hg19: chr4-109739467;