4-108845243-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198721.4(COL25A1):c.1524T>A(p.Asn508Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL25A1 NM_198721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.731

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16879147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL25A1	NM_198721.4	c.1524T>A	p.Asn508Lys	missense_variant	29/38	ENST00000399132.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL25A1	ENST00000399132.6	c.1524T>A	p.Asn508Lys	missense_variant	29/38	5	NM_198721.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1524T>A (p.N508K) alteration is located in exon 29 (coding exon 28) of the COL25A1 gene. This alteration results from a T to A substitution at nucleotide position 1524, causing the asparagine (N) at amino acid position 508 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T;D;T;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.59	D;N;N
PrimateAI	Uncertain	0.66	T
Polyphen		0.91, 0.97	.;.;P;.;D
Vest4		0.62, 0.60, 0.61
MutPred		0.36		Gain of glycosylation at N508 (P = 0.0044);.;Gain of glycosylation at N508 (P = 0.0044);.;Gain of glycosylation at N508 (P = 0.0044);
MVP		0.70
MPC		0.39
ClinPred		0.61	D
GERP RS		-3.0
Varity_R		0.14
gMVP		0.40

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-109766399;