rs10012573

Variant names:

• chr4-109027430-A-C
• rs10012573
• NM_198721.4:c.421-17055T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-109027430-A-C
• chr4-109027430-A-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.421-17055T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 130,046 control chromosomes in the GnomAD database, including 387 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 0.075 (387 hom., cov: 32)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171
• 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

LOC124900756 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.421-17055T>G		intron	N/A	NP_942014.1
	COL25A1	NM_001256074.3		c.421-17055T>G		intron	N/A	NP_001243003.1
	COL25A1	NM_032518.4		c.421-17055T>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.421-17055T>G		intron	N/A	ENSP00000382083.1
	COL25A1	ENST00000642955.1		c.421-17055T>G		intron	N/A	ENSP00000495847.1
	COL25A1	ENST00000399127.5	TSL:5	c.421-17055T>G		intron	N/A	ENSP00000382078.1

Frequencies

GnomAD3 genomes AF: 0.0753 AC: 9779 AN: 129952 Hom.: 386 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0571

Gnomad ASJ AF: 0.0913

Gnomad EAS AF: 0.000262

Gnomad SAS AF: 0.0615

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0902

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.0724

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

GnomAD4 genome AF: 0.0753 AC: 9786 AN: 130046 Hom.: 387 Cov.: 32 AF XY: 0.0727 AC XY: 4593 AN XY: 63154

African (AFR) AF: 0.139 AC: 4010 AN: 28830

American (AMR) AF: 0.0571 AC: 703 AN: 12322

Ashkenazi Jewish (ASJ) AF: 0.0913 AC: 295 AN: 3230

East Asian (EAS) AF: 0.000262 AC: 1 AN: 3814

South Asian (SAS) AF: 0.0603 AC: 240 AN: 3978

European-Finnish (FIN) AF: 0.0247 AC: 246 AN: 9954

Middle Eastern (MID) AF: 0.104 AC: 26 AN: 250

European-Non Finnish (NFE) AF: 0.0629 AC: 4086 AN: 64972

Other (OTH) AF: 0.0748 AC: 138 AN: 1846

Alfa AF: 0.0595 Hom.: 248

Bravo AF: 0.0669

Asia WGS AF: 0.0420 AC: 146 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.31
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: rs10012573; hg19: chr4-109948586;