chr4-108912159-C-G

Variant names:

• chr4-108912159-C-G
• rs1405152
• NM_198721.4:c.780+6013G>C

Variant summary

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

The NM_198721.4(COL25A1):​c.780+6013G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 151,894 control chromosomes in the GnomAD database, including 37,953 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 0.70 (37953 hom., cov: 31)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409
• 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), 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.780+6013G>C		intron_variant	Intron 13 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.780+6013G>C		intron_variant	Intron 13 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105507 AN: 151776 Hom.: 37937 Cov.: 31

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.935

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.889

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.723

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

GnomAD4 genome AF: 0.695 AC: 105568 AN: 151894 Hom.: 37953 Cov.: 31 AF XY: 0.706 AC XY: 52440 AN XY: 74242

African (AFR) AF: 0.503 AC: 20827 AN: 41412

American (AMR) AF: 0.775 AC: 11830 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2529 AN: 3464

East Asian (EAS) AF: 0.935 AC: 4815 AN: 5150

South Asian (SAS) AF: 0.812 AC: 3910 AN: 4818

European-Finnish (FIN) AF: 0.889 AC: 9394 AN: 10568

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49867 AN: 67904

Other (OTH) AF: 0.722 AC: 1523 AN: 2110

Alfa AF: 0.698 Hom.: 4484

Bravo AF: 0.679

Asia WGS AF: 0.847 AC: 2935 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.53
DANN	Benign	0.38
PhyloP100		-0.41
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: rs1405152; hg19: chr4-109833315;