chr4-109109254-G-A

Variant names:

• chr4-109109254-G-A
• rs4368681
• NM_198721.4:c.368-59075C>T

Variant summary

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

The NM_198721.4(COL25A1):​c.368-59075C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,978 control chromosomes in the GnomAD database, including 20,822 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 0.48 (20822 hom., cov: 32)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.664 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.368-59075C>T		intron	N/A	NP_942014.1
	COL25A1	NM_001256074.3		c.368-59075C>T		intron	N/A	NP_001243003.1
	COL25A1	NM_032518.4		c.368-59075C>T		intron	N/A	NP_115907.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL25A1	ENST00000399132.6	TSL:5 MANE Select	c.368-59075C>T		intron	N/A	ENSP00000382083.1
	COL25A1	ENST00000642955.1		c.368-59075C>T		intron	N/A	ENSP00000495847.1
	COL25A1	ENST00000399127.5	TSL:5	c.368-59075C>T		intron	N/A	ENSP00000382078.1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72896 AN: 151860 Hom.: 20826 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.479 AC: 72871 AN: 151978 Hom.: 20822 Cov.: 32 AF XY: 0.471 AC XY: 34960 AN XY: 74256

African (AFR) AF: 0.177 AC: 7335 AN: 41448

American (AMR) AF: 0.419 AC: 6396 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1928 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1953 AN: 5158

South Asian (SAS) AF: 0.478 AC: 2298 AN: 4810

European-Finnish (FIN) AF: 0.538 AC: 5664 AN: 10536

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45504 AN: 67978

Other (OTH) AF: 0.496 AC: 1047 AN: 2110

Alfa AF: 0.605 Hom.: 127300

Bravo AF: 0.456

Asia WGS AF: 0.413 AC: 1442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.81
PhyloP100		0.24
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: rs4368681; hg19: chr4-110030410;