rs2194860

Variant names:

• chr4-109027355-G-A
• rs2194860
• NM_198721.4:c.421-16980C>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.421-16980C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 151,940 control chromosomes in the GnomAD database, including 12,666 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 0.35 (12666 hom., cov: 31)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 5 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

LOC124900756 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.421-16980C>T		intron_variant	Intron 5 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.421-16980C>T		intron_variant	Intron 5 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52541 AN: 151822 Hom.: 12614 Cov.: 31

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.347 AC: 52663 AN: 151940 Hom.: 12666 Cov.: 31 AF XY: 0.356 AC XY: 26417 AN XY: 74296

African (AFR) AF: 0.625 AC: 25864 AN: 41390

American (AMR) AF: 0.449 AC: 6858 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1199 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3314 AN: 5138

South Asian (SAS) AF: 0.402 AC: 1935 AN: 4812

European-Finnish (FIN) AF: 0.205 AC: 2173 AN: 10576

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10256 AN: 67972

Other (OTH) AF: 0.365 AC: 770 AN: 2108

Alfa AF: 0.233 Hom.: 10967

Bravo AF: 0.382

Asia WGS AF: 0.550 AC: 1910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.8
DANN	Benign	0.72
PhyloP100		0.17
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: rs2194860; hg19: chr4-109948511;