chr9-134801982-G-GC

Variant names:

• chr9-134801982-G-GC
• rs764693725
• NM_000093.5:c.2988dupC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_000093.5(COL5A1):​c.2988dupC​(p.Gly997ArgfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: COL5A1 NM_000093.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -7.85

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.
• PP5: Variant 9-134801982-G-GC is Pathogenic according to our data. Variant chr9-134801982-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 459667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2988dupC	p.Gly997ArgfsTer17	frameshift_variant	Exon 38 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2988dupC	p.Gly997ArgfsTer17	frameshift_variant	Exon 38 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.2988dupC	p.Gly997ArgfsTer17	frameshift_variant	Exon 38 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2988dupC	p.Gly997ArgfsTer17	frameshift_variant	Exon 38 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2988dupC	p.Gly997ArgfsTer17	frameshift_variant	Exon 38 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460988 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726804

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: 0.000266

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000334 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Oct 08, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 459667; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22696272, 23587214) -

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

Feb 10, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly997Argfs*17) in the COL5A1 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with Ehlers–Danlos syndrome (PMID: 22696272, 23587214). ClinVar contains an entry for this variant (Variation ID: 459667). Loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs764693725; hg19: chr9-137693828;