4-108859974-C-T

Position:

• chr4-108859974-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.1243-241G>A		intron_variant		ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.1243-241G>A		intron_variant		5	NM_198721.4	ENSP00000382083

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

Gnomad4 AFR AF: 0.284

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.239

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.268

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.052
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs10001134; hg19: chr4-109781130;