4-109087431-C-T

Variant names:

• chr4-109087431-C-T
• rs13115905
• NM_198721.4:c.368-37252G>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.368-37252G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 151,970 control chromosomes in the GnomAD database, including 20,543 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 0.48 (20543 hom., cov: 31)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 3 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), Ambry Genetics, G2P, Genomics England PanelApp
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.368-37252G>A		intron_variant	Intron 3 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.368-37252G>A		intron_variant	Intron 3 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72558 AN: 151852 Hom.: 20546 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.655

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.477 AC: 72536 AN: 151970 Hom.: 20543 Cov.: 31 AF XY: 0.469 AC XY: 34805 AN XY: 74248

African (AFR) AF: 0.182 AC: 7570 AN: 41482

American (AMR) AF: 0.412 AC: 6285 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1920 AN: 3468

East Asian (EAS) AF: 0.369 AC: 1900 AN: 5148

South Asian (SAS) AF: 0.472 AC: 2269 AN: 4804

European-Finnish (FIN) AF: 0.540 AC: 5692 AN: 10548

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45127 AN: 67944

Other (OTH) AF: 0.494 AC: 1044 AN: 2112

Alfa AF: 0.524 Hom.: 3877

Bravo AF: 0.453

Asia WGS AF: 0.406 AC: 1415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.4
DANN	Benign	0.56
PhyloP100		-0.24
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: rs13115905; hg19: chr4-110008587;