4-108809654-A-G

Variant names:

• chr4-108809654-A-G
• rs1812590
• NM_198721.4:c.*4273T>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.*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
• Publications: 2 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=-0.7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198721.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	NM_198721.4	MANE Select	c.*4273T>C		3_prime_UTR	Exon 38 of 38	NP_942014.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	ENST00000399132.6	TSL:5 MANE Select	c.*4273T>C		3_prime_UTR	Exon 38 of 38	ENSP00000382083.1
	COL25A1	ENST00000642955.1		c.*4273T>C		3_prime_UTR	Exon 39 of 39	ENSP00000495847.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.302 AC: 12506 AN: 41442

American (AMR) AF: 0.508 AC: 7758 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2038 AN: 3464

East Asian (EAS) AF: 0.527 AC: 2721 AN: 5168

South Asian (SAS) AF: 0.594 AC: 2863 AN: 4822

European-Finnish (FIN) AF: 0.572 AC: 6036 AN: 10544

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.568 AC: 38510 AN: 67794

Other (OTH) AF: 0.502 AC: 1057 AN: 2106

Alfa AF: 0.536 Hom.: 54740

Bravo AF: 0.475

Asia WGS AF: 0.564 AC: 1958 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.77
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs1812590; hg19: chr4-109730810;