4-108817411-C-G

Variant summary

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

The NM_198721.4(COL25A1):c.1948G>C(p.Gly650Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL25A1 NM_198721.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL25A1	NM_198721.4	c.1948G>C	p.Gly650Arg	missense_variant	37/38	ENST00000399132.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL25A1	ENST00000399132.6	c.1948G>C	p.Gly650Arg	missense_variant	37/38	5	NM_198721.4
COL25A1	ENST00000642955.1	c.2074G>C	p.Gly692Arg	missense_variant	38/39			P1
COL25A1	ENST00000512961.5	c.73G>C	p.Gly25Arg	missense_variant	2/3	5
COL25A1	ENST00000494183.5	c.*242G>C		3_prime_UTR_variant, NMD_transcript_variant	35/37	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 06, 2022

The c.1948G>C (p.G650R) alteration is located in exon 37 (coding exon 36) of the COL25A1 gene. This alteration results from a G to C substitution at nucleotide position 1948, causing the glycine (G) at amino acid position 650 to be replaced by an arginine (R). 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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	31
Dann	Uncertain	0.98
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	-0.071	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	.;.;D
Vest4		0.89, 0.85
MutPred		0.36		.;.;Gain of solvent accessibility (P = 0.0037);
MVP		0.94
MPC		1.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr4-109738567;