rs1963939

Variant names:

• chr4-108818311-A-G
• rs1963939
• NM_198721.4:c.1924-876T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-108818311-A-G
• chr4-108818311-A-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.1924-876T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 151,558 control chromosomes in the GnomAD database, including 19,165 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 0.49 (19165 hom., cov: 33)
• Consequence: COL25A1 NM_198721.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0160
• 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=-0.58).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL25A1	NM_198721.4	c.1924-876T>C		intron_variant	Intron 36 of 37	ENST00000399132.6	NP_942014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL25A1	ENST00000399132.6	c.1924-876T>C		intron_variant	Intron 36 of 37	5	NM_198721.4	ENSP00000382083.1
COL25A1	ENST00000642955.1	c.2050-876T>C		intron_variant	Intron 37 of 38			ENSP00000495847.1
COL25A1	ENST00000512961.5	c.46-876T>C		intron_variant	Intron 1 of 2	5		ENSP00000426841.1
COL25A1	ENST00000494183.5	n.*218-876T>C		intron_variant	Intron 34 of 36	5		ENSP00000437131.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74474 AN: 151438 Hom.: 19158 Cov.: 33

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.509

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

GnomAD4 genome AF: 0.491 AC: 74490 AN: 151558 Hom.: 19165 Cov.: 33 AF XY: 0.494 AC XY: 36541 AN XY: 74036

African (AFR) AF: 0.314 AC: 12990 AN: 41396

American (AMR) AF: 0.511 AC: 7788 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2032 AN: 3458

East Asian (EAS) AF: 0.523 AC: 2679 AN: 5124

South Asian (SAS) AF: 0.589 AC: 2832 AN: 4806

European-Finnish (FIN) AF: 0.568 AC: 5931 AN: 10434

Middle Eastern (MID) AF: 0.645 AC: 187 AN: 290

European-Non Finnish (NFE) AF: 0.568 AC: 38481 AN: 67796

Other (OTH) AF: 0.504 AC: 1063 AN: 2108

Alfa AF: 0.520 Hom.: 2612

Bravo AF: 0.481

Asia WGS AF: 0.562 AC: 1937 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.5
DANN	Benign	0.86
PhyloP100		0.016
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: rs1963939; hg19: chr4-109739467;