rs121912933

chr9-134774901-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000093.5(COL5A1):c.2374C>T(p.Arg792Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.39

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 9-134774901-C-T is Pathogenic according to our data. Variant chr9-134774901-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.2374C>T	p.Arg792Ter	stop_gained	27/66	ENST00000371817.8
LOC124902301	XR_007061843.1	n.980G>A		non_coding_transcript_exon_variant	1/2
COL5A1	NM_001278074.1	c.2374C>T	p.Arg792Ter	stop_gained	27/66
COL5A1	XM_017014266.3	c.2374C>T	p.Arg792Ter	stop_gained	27/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.2374C>T	p.Arg792Ter	stop_gained	27/66	1	NM_000093.5	P4
	ENST00000666389.1	n.771G>A		non_coding_transcript_exon_variant	1/2
COL5A1	ENST00000371820.4	c.2374C>T	p.Arg792Ter	stop_gained	27/66	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 25, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 17191). This premature translational stop signal has been observed in individual(s) with Ehlers-Danlos syndrome (PMID: 10777716, 31829210). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg792*) 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). -

Ehlers-Danlos syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	48
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
Vest4		0.93
GERP RS		3.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121912933; hg19: chr9-137666747; COSMIC: COSV100880190;