chr4-109152169-T-C

Variant names:

• chr4-109152169-T-C
• rs2704108
• NM_198721.4:c.368-101990A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198721.4(COL25A1):​c.368-101990A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 151,774 control chromosomes in the GnomAD database, including 30,653 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 0.63 (30653 hom., cov: 31)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 0 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), Genomics England PanelApp, G2P, Ambry Genetics
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	NM_198721.4	MANE Select	c.368-101990A>G		intron	N/A	NP_942014.1	Q9BXS0-1
	COL25A1	NM_001256074.3		c.368-101990A>G		intron	N/A	NP_001243003.1	A8MWQ5
	COL25A1	NM_032518.4		c.368-101990A>G		intron	N/A	NP_115907.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	ENST00000399132.6	TSL:5 MANE Select	c.368-101990A>G		intron	N/A	ENSP00000382083.1	Q9BXS0-1
	COL25A1	ENST00000642955.1		c.368-101990A>G		intron	N/A	ENSP00000495847.1	A0A2R8Y760
	COL25A1	ENST00000399127.5	TSL:5	c.368-101990A>G		intron	N/A	ENSP00000382078.1	A8MWQ5

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95613 AN: 151660 Hom.: 30629 Cov.: 31

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.666

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.630 AC: 95677 AN: 151774 Hom.: 30653 Cov.: 31 AF XY: 0.624 AC XY: 46272 AN XY: 74114

African (AFR) AF: 0.556 AC: 23025 AN: 41422

American (AMR) AF: 0.605 AC: 9228 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1787 AN: 3466

East Asian (EAS) AF: 0.750 AC: 3872 AN: 5164

South Asian (SAS) AF: 0.709 AC: 3412 AN: 4814

European-Finnish (FIN) AF: 0.527 AC: 5511 AN: 10452

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.688 AC: 46669 AN: 67880

Other (OTH) AF: 0.670 AC: 1414 AN: 2110

Alfa AF: 0.554 Hom.: 1723

Bravo AF: 0.628

Asia WGS AF: 0.745 AC: 2586 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.71
DANN	Benign	0.61
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2704108; hg19: chr4-110073325;