rs144844792

chr9-134727372-C-Achr9-134727372-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000093.5(COL5A1):c.761C>A(p.Ser254Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S254S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A1 NM_000093.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.66

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-134727372-C-A is Pathogenic according to our data. Variant chr9-134727372-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 964823.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.761C>A	p.Ser254Ter	stop_gained	5/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.761C>A	p.Ser254Ter	stop_gained	5/66
COL5A1	XM_017014266.3	c.761C>A	p.Ser254Ter	stop_gained	5/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.761C>A	p.Ser254Ter	stop_gained	5/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.761C>A	p.Ser254Ter	stop_gained	5/66	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 964823). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser254*) in the COL5A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	0.99
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A
Vest4		0.84
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs144844792; hg19: chr9-137619218;