NM_198721.4:c.412+755A>G

Variant names:

• chr4-109049380-T-C
• rs3096483
• NM_198721.4:c.412+755A>G

Variant summary

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

The NM_198721.4(COL25A1):​c.412+755A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 152,036 control chromosomes in the GnomAD database, including 19,287 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 (19287 hom., cov: 32)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 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.412+755A>G		intron	N/A	NP_942014.1
	COL25A1	NM_001256074.3		c.412+755A>G		intron	N/A	NP_001243003.1
	COL25A1	NM_032518.4		c.412+755A>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.412+755A>G		intron	N/A	ENSP00000382083.1
	COL25A1	ENST00000642955.1		c.412+755A>G		intron	N/A	ENSP00000495847.1
	COL25A1	ENST00000399127.5	TSL:5	c.412+755A>G		intron	N/A	ENSP00000382078.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73429 AN: 151916 Hom.: 19250 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.484 AC: 73525 AN: 152036 Hom.: 19287 Cov.: 32 AF XY: 0.485 AC XY: 36074 AN XY: 74306

African (AFR) AF: 0.665 AC: 27602 AN: 41508

American (AMR) AF: 0.558 AC: 8518 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1557 AN: 3466

East Asian (EAS) AF: 0.662 AC: 3415 AN: 5160

South Asian (SAS) AF: 0.467 AC: 2250 AN: 4820

European-Finnish (FIN) AF: 0.329 AC: 3478 AN: 10570

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25110 AN: 67930

Other (OTH) AF: 0.489 AC: 1032 AN: 2112

Alfa AF: 0.451 Hom.: 2912

Bravo AF: 0.511

Asia WGS AF: 0.573 AC: 1991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.65
PhyloP100		0.44
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: rs3096483; hg19: chr4-109970536;