4-108919403-A-G

Variant names:

• chr4-108919403-A-G
• rs13134663
• NM_198721.4:c.735+1175T>C

Variant summary

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

The NM_198721.4(COL25A1):​c.735+1175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,978 control chromosomes in the GnomAD database, including 19,374 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 0.47 (19374 hom., cov: 31)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.02
• Publications: 4 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.735+1175T>C		intron_variant	Intron 12 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.735+1175T>C		intron_variant	Intron 12 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71288 AN: 151860 Hom.: 19366 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.492

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

GnomAD4 genome AF: 0.469 AC: 71328 AN: 151978 Hom.: 19374 Cov.: 31 AF XY: 0.486 AC XY: 36092 AN XY: 74254

African (AFR) AF: 0.214 AC: 8896 AN: 41480

American (AMR) AF: 0.576 AC: 8789 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1767 AN: 3468

East Asian (EAS) AF: 0.933 AC: 4801 AN: 5148

South Asian (SAS) AF: 0.755 AC: 3631 AN: 4812

European-Finnish (FIN) AF: 0.677 AC: 7140 AN: 10542

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34568 AN: 67950

Other (OTH) AF: 0.494 AC: 1044 AN: 2114

Alfa AF: 0.473 Hom.: 3138

Bravo AF: 0.451

Asia WGS AF: 0.803 AC: 2790 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.54
PhyloP100		-5.0
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: rs13134663; hg19: chr4-109840559;