chr4-108859974-C-T

Variant names:

• chr4-108859974-C-T
• rs10001134
• NM_198721.4:c.1243-241G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198721.4(COL25A1):​c.1243-241G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 151,970 control chromosomes in the GnomAD database, including 5,194 homozygotes. 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: 𝑓 0.26 (5194 hom., cov: 32)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

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.1243-241G>A		intron	N/A	NP_942014.1	Q9BXS0-1
	COL25A1	NM_001256074.3		c.1186-241G>A		intron	N/A	NP_001243003.1	A8MWQ5
	COL25A1	NM_032518.4		c.1243-241G>A		intron	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.1243-241G>A		intron	N/A	ENSP00000382083.1	Q9BXS0-1
	COL25A1	ENST00000642955.1		c.1243-241G>A		intron	N/A	ENSP00000495847.1	A0A2R8Y760
	COL25A1	ENST00000399127.5	TSL:5	c.1186-241G>A		intron	N/A	ENSP00000382078.1	A8MWQ5

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38769 AN: 151852 Hom.: 5190 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.255 AC: 38810 AN: 151970 Hom.: 5194 Cov.: 32 AF XY: 0.246 AC XY: 18290 AN XY: 74258

African (AFR) AF: 0.284 AC: 11775 AN: 41396

American (AMR) AF: 0.198 AC: 3030 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 828 AN: 3470

East Asian (EAS) AF: 0.101 AC: 524 AN: 5184

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4824

European-Finnish (FIN) AF: 0.136 AC: 1440 AN: 10552

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19121 AN: 67952

Other (OTH) AF: 0.268 AC: 565 AN: 2112

Alfa AF: 0.275 Hom.: 1097

Bravo AF: 0.258

Asia WGS AF: 0.183 AC: 635 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.052
DANN	Benign	0.33
PhyloP100		-1.2
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: rs10001134; hg19: chr4-109781130;