4-108809654-A-G

Position:

• chr4-108809654-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198721.4(COL25A1):​c.*4273T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 151,806 control chromosomes in the GnomAD database, including 19,141 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 0.49 (19141 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: COL25A1 NM_198721.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

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=-0.7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.*4273T>C		3_prime_UTR_variant	38/38	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.*4273T>C		3_prime_UTR_variant	38/38	5	NM_198721.4	ENSP00000382083
COL25A1	ENST00000642955.1	c.*4273T>C		3_prime_UTR_variant	39/39			ENSP00000495847	P1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74176 AN: 151688 Hom.: 19134 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.506

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.489 AC: 74189 AN: 151806 Hom.: 19141 Cov.: 32 AF XY: 0.491 AC XY: 36436 AN XY: 74160

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.588

Gnomad4 EAS AF: 0.527

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.502

Alfa AF: 0.544 Hom.: 22586

Bravo AF: 0.475

Asia WGS AF: 0.564 AC: 1958 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1812590; hg19: chr4-109730810;