rs886042173

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000093.5(COL5A1):c.2034+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

COL5A1
NM_000093.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.76

Publications

0 publications found

Variant links:

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
Ehlers-Danlos syndrome, classic type, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
arterial disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL5A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.008156607 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of 8, new splice context is: tctGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-134763738-G-A is Pathogenic according to our data. Variant chr9-134763738-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 281486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.2034+1G>A	splice_donor_variant, intron_variant	Intron 20 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.2034+1G>A	splice_donor_variant, intron_variant	Intron 20 of 65		NP_001265003.1
COL5A1	XM_017014266.3 link	c.2034+1G>A	splice_donor_variant, intron_variant	Intron 20 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.2034+1G>A		splice_donor_variant, intron_variant	Intron 20 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.2034+1G>A		splice_donor_variant, intron_variant	Intron 20 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Dec 07, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant in a gene for which loss of function is a known mechanism of disease; Damages or destroys the splice donor site in intron 20, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function (PMID: 22696272; HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34265140, 35128800, 23587214) -

Jun 23, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1

Pathogenic:2

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 20 of the COL5A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features consistent with Ehlers-Danlos syndrome (PMID: 27011056, 34265140; Invitae). ClinVar contains an entry for this variant (Variation ID: 281486). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 18, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1_VStr, PM2_M, PP3_Sup -

Ehlers-Danlos syndrome

Pathogenic:1

Dec 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

PhyloP100

5.8

GERP RS

3.9

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 7

DS_DL_spliceai

0.94

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over