NM_198721.4:c.420+9082T>C

Variant names:

• chr4-109039086-A-G
• rs794149
• NM_198721.4:c.420+9082T>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.420+9082T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 151,518 control chromosomes in the GnomAD database, including 21,894 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 0.51 (21894 hom., cov: 30)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.734
• Publications: 3 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.420+9082T>C		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.420+9082T>C		intron_variant	Intron 5 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77343 AN: 151402 Hom.: 21846 Cov.: 30

Gnomad AFR AF: 0.746

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.505

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

GnomAD4 genome AF: 0.511 AC: 77462 AN: 151518 Hom.: 21894 Cov.: 30 AF XY: 0.513 AC XY: 37989 AN XY: 74016

African (AFR) AF: 0.746 AC: 30871 AN: 41366

American (AMR) AF: 0.570 AC: 8679 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3416 AN: 5132

South Asian (SAS) AF: 0.476 AC: 2276 AN: 4784

European-Finnish (FIN) AF: 0.338 AC: 3532 AN: 10464

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25468 AN: 67766

Other (OTH) AF: 0.510 AC: 1075 AN: 2106

Alfa AF: 0.459 Hom.: 3008

Bravo AF: 0.539

Asia WGS AF: 0.584 AC: 2028 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.32
DANN	Benign	0.37
PhyloP100		-0.73
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: rs794149; hg19: chr4-109960242;