rs765079080

Positions:

• chr9-134795057-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000093.5(COL5A1):​c.2701-25T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.385

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-134795057-T-G is Pathogenic according to our data. Variant chr9-134795057-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 17188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134795057-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.2701-25T>G		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.2701-25T>G		intron_variant
COL5A1	XM_017014266.3	c.2701-25T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.2701-25T>G		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.2701-25T>G		intron_variant		2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250602 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460902 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 33, but is expected to preserve the integrity of the reading-frame (PMID: 9683580). ClinVar contains an entry for this variant (Variation ID: 17188). This variant has been observed in individuals with Ehlers-Danlos Syndrome (PMID: 9683580). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs765079080, gnomAD 0.0009%). This sequence change falls in intron 32 of the COL5A1 gene. It does not directly change the encoded amino acid sequence of the COL5A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 16, 2021	The COL5A1 c.2701-25T>G variant is classified as a PATHOGENIC variant (PS3, PP1_strong, PP5, PM2) This variant is a single nucleotide change from a thymine to a guanine at position 2701-25 in intron 32 of the COL5A1 gene. This variant is located in an intronic branch site and has been shown to lead to exon 33 skipping in vitro (PMID: 9683580) (PS3). The variant has been reported in multiple individuals with Ehlers-Danlos syndrome (EDS), and it has been observed to segregate with EDS in two large multigenerational families (PMID: 9683580) (PP1_strong). The variant is in dbSNP (rs765079080) but is absent from population databases (PM2). The variant has been reported in ClinVar and HGMD disease databases as a pathogenic variant (PP5). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.87
BranchPoint Hunter		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs765079080; hg19: chr9-137686903;