rs11942576

Variant names:

• chr4-108841762-C-A
• rs11942576
• NM_198721.4:c.1630-41G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-108841762-C-A
• chr4-108841762-C-G
• chr4-108841762-C-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.1630-41G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,508,322 control chromosomes in the GnomAD database, including 300,132 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 0.62 (29461 hom., cov: 31)
  • Exomes 𝑓: 0.63 (270671 hom.)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.755 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.1630-41G>T		intron	N/A	NP_942014.1	Q9BXS0-1
	COL25A1	NM_001256074.3		c.1549-41G>T		intron	N/A	NP_001243003.1	A8MWQ5
	COL25A1	NM_032518.4		c.1630-41G>T		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.1630-41G>T		intron	N/A	ENSP00000382083.1	Q9BXS0-1
	COL25A1	ENST00000642955.1		c.1630-41G>T		intron	N/A	ENSP00000495847.1	A0A2R8Y760
	COL25A1	ENST00000399127.5	TSL:5	c.1549-41G>T		intron	N/A	ENSP00000382078.1	A8MWQ5

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94082 AN: 151782 Hom.: 29437 Cov.: 31

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.637

GnomAD2 exomes AF: 0.663 AC: 162521 AN: 244972 AF XY: 0.667

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.729

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.633

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.629 AC: 853164 AN: 1356424 Hom.: 270671 Cov.: 20 AF XY: 0.633 AC XY: 431100 AN XY: 680744

African (AFR) AF: 0.540 AC: 17018 AN: 31530

American (AMR) AF: 0.723 AC: 32048 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 16645 AN: 25430

East Asian (EAS) AF: 0.579 AC: 22589 AN: 39004

South Asian (SAS) AF: 0.760 AC: 63494 AN: 83598

European-Finnish (FIN) AF: 0.676 AC: 35966 AN: 53184

Middle Eastern (MID) AF: 0.676 AC: 3750 AN: 5544

European-Non Finnish (NFE) AF: 0.615 AC: 625926 AN: 1017186

Other (OTH) AF: 0.631 AC: 35728 AN: 56620

GnomAD4 genome AF: 0.620 AC: 94148 AN: 151898 Hom.: 29461 Cov.: 31 AF XY: 0.626 AC XY: 46443 AN XY: 74218

African (AFR) AF: 0.541 AC: 22422 AN: 41410

American (AMR) AF: 0.685 AC: 10460 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2273 AN: 3472

East Asian (EAS) AF: 0.651 AC: 3354 AN: 5152

South Asian (SAS) AF: 0.776 AC: 3732 AN: 4810

European-Finnish (FIN) AF: 0.688 AC: 7252 AN: 10542

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42464 AN: 67936

Other (OTH) AF: 0.637 AC: 1341 AN: 2106

Alfa AF: 0.621 Hom.: 62769

Bravo AF: 0.616

Asia WGS AF: 0.724 AC: 2520 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.34
DANN	Benign	0.60
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11942576; hg19: chr4-109762918; COSMIC: COSV67645829;