rs1859143

Positions:

• chr4-109302164-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_198721.4(COL25A1):​c.-57+5G>A variant causes a splice donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.4850
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.-57+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.-57+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_198721.4	ENSP00000382083

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

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.482

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.467

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

Gnomad4 AFR AF: 0.828

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.407

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.441

Gnomad4 OTH AF: 0.518

Alfa AF: 0.462 Hom.: 22606

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

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

Publications

LitVar

Other links and lift over

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