4-108852290-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_198721.4(COL25A1):c.1345-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,589,470 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: COL25A1 NM_198721.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.007376
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 4-108852290-G-C is Benign according to our data. Variant chr4-108852290-G-C is described in ClinVar as [Benign]. Clinvar id is 767967.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1748/152158) while in subpopulation AFR AF= 0.0398 (1654/41532). AF 95% confidence interval is 0.0382. There are 32 homozygotes in gnomad4. There are 790 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL25A1	NM_198721.4	c.1345-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000399132.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL25A1	ENST00000399132.6	c.1345-10C>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_198721.4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1744 AN: 152040 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00304 AC: 697 AN: 228912 Hom.: 14 AF XY: 0.00217 AC XY: 271 AN XY: 124614

Gnomad AFR exome AF: 0.0418

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000757

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000932

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00116 AC: 1672 AN: 1437312 Hom.: 34 Cov.: 28 AF XY: 0.00105 AC XY: 750 AN XY: 715220

Gnomad4 AFR exome AF: 0.0407

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000870

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.0115 AC: 1748 AN: 152158 Hom.: 32 Cov.: 33 AF XY: 0.0106 AC XY: 790 AN XY: 74390

Gnomad4 AFR AF: 0.0398

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00590 Hom.: 3

Bravo AF: 0.0136

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0074
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114761964; hg19: chr4-109773446;