rs1859143

Variant names:

• chr4-109302164-C-T
• rs1859143
• NM_198721.4:c.-57+5G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_198721.4(COL25A1):​c.-57+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,046,204 control chromosomes in the GnomAD database, including 119,683 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 0.54 (25049 hom., cov: 33)
  • Exomes 𝑓: 0.45 (94634 hom.)
• Consequence: COL25A1 NM_198721.4 splice_region, intron
• Scores: Splicing: ADA: 0.4850
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• Publications: 7 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.-57+5G>A		splice_region_variant, intron_variant	Intron 1 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.-57+5G>A		splice_region_variant, intron_variant	Intron 1 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82780 AN: 152032 Hom.: 24988 Cov.: 33

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.454 AC: 406159 AN: 894054 Hom.: 94634 Cov.: 12 AF XY: 0.454 AC XY: 201823 AN XY: 444816

African (AFR) AF: 0.842 AC: 17460 AN: 20748

American (AMR) AF: 0.431 AC: 8233 AN: 19098

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 6534 AN: 16352

East Asian (EAS) AF: 0.403 AC: 13272 AN: 32932

South Asian (SAS) AF: 0.482 AC: 25420 AN: 52780

European-Finnish (FIN) AF: 0.418 AC: 12601 AN: 30134

Middle Eastern (MID) AF: 0.420 AC: 1195 AN: 2846

European-Non Finnish (NFE) AF: 0.446 AC: 302482 AN: 678540

Other (OTH) AF: 0.467 AC: 18962 AN: 40624

GnomAD4 genome AF: 0.545 AC: 82914 AN: 152150 Hom.: 25049 Cov.: 33 AF XY: 0.540 AC XY: 40148 AN XY: 74378

African (AFR) AF: 0.828 AC: 34388 AN: 41554

American (AMR) AF: 0.443 AC: 6778 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1414 AN: 3470

East Asian (EAS) AF: 0.411 AC: 2115 AN: 5152

South Asian (SAS) AF: 0.474 AC: 2283 AN: 4816

European-Finnish (FIN) AF: 0.414 AC: 4378 AN: 10576

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.441 AC: 29984 AN: 67968

Other (OTH) AF: 0.518 AC: 1096 AN: 2114

Alfa AF: 0.473 Hom.: 30243

Bravo AF: 0.558

Asia WGS AF: 0.471 AC: 1639 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.92
PhyloP100		-1.6
PromoterAI		-0.0068	Neutral
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.46		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1859143; hg19: chr4-110223320; COSMIC: COSV67658092; COSMIC: COSV67658092;