rs2030844

Variant names:

• chr4-108920882-T-A
• rs2030844
• NM_198721.4:c.709-278A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-108920882-T-A
• chr4-108920882-T-C
• chr4-108920882-T-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.709-278A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 282,734 control chromosomes in the GnomAD database, including 77,674 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 0.71 (39386 hom., cov: 33)
  • Exomes 𝑓: 0.76 (38288 hom.)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.510
• Publications: 1 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.709-278A>T		intron_variant	Intron 11 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.709-278A>T		intron_variant	Intron 11 of 37	5	NM_198721.4	ENSP00000382083.1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107355 AN: 151968 Hom.: 39367 Cov.: 33

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.718

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.895

Gnomad MID AF: 0.739

Gnomad NFE AF: 0.746

Gnomad OTH AF: 0.725

GnomAD4 exome AF: 0.757 AC: 98948 AN: 130648 Hom.: 38288 AF XY: 0.756 AC XY: 50671 AN XY: 67048

African (AFR) AF: 0.488 AC: 2210 AN: 4532

American (AMR) AF: 0.797 AC: 3348 AN: 4202

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 3681 AN: 5090

East Asian (EAS) AF: 1.00 AC: 12576 AN: 12578

South Asian (SAS) AF: 0.810 AC: 2342 AN: 2892

European-Finnish (FIN) AF: 0.873 AC: 6419 AN: 7352

Middle Eastern (MID) AF: 0.737 AC: 607 AN: 824

European-Non Finnish (NFE) AF: 0.727 AC: 61273 AN: 84306

Other (OTH) AF: 0.732 AC: 6492 AN: 8872

GnomAD4 genome AF: 0.706 AC: 107422 AN: 152086 Hom.: 39386 Cov.: 33 AF XY: 0.718 AC XY: 53383 AN XY: 74342

African (AFR) AF: 0.505 AC: 20929 AN: 41470

American (AMR) AF: 0.797 AC: 12169 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2535 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5157 AN: 5172

South Asian (SAS) AF: 0.839 AC: 4047 AN: 4824

European-Finnish (FIN) AF: 0.895 AC: 9486 AN: 10594

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.746 AC: 50693 AN: 67966

Other (OTH) AF: 0.726 AC: 1536 AN: 2116

Alfa AF: 0.710 Hom.: 4869

Bravo AF: 0.692

Asia WGS AF: 0.892 AC: 3091 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.59
DANN	Benign	0.65
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: rs2030844; hg19: chr4-109842038;