chr9-134785001-C-T

Variant names:

• chr9-134785001-C-T
• rs370547479
• NM_000093.5:c.2497C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000093.5(COL5A1):​c.2497C>T​(p.Pro833Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P833L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000093.5
• BP6: Variant 9-134785001-C-T is Benign according to our data. Variant chr9-134785001-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529258.
• BS2: High AC in GnomAdExome4 at 78 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.2497C>T	p.Pro833Ser	missense	Exon 30 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.2497C>T	p.Pro833Ser	missense	Exon 30 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.2497C>T	p.Pro833Ser	missense	Exon 30 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2497C>T	p.Pro833Ser	missense	Exon 30 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2488C>T	p.Pro830Ser	missense	Exon 30 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 249998 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1460968 Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 31 AN XY: 726770

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Ehlers-Danlos syndrome, classic type, 1 (2)
-	1	1	not provided (2)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.38
Sift	Benign	0.10	T
Sift4G	Benign	0.39	T
Polyphen		0.85	P
Vest4		0.58
MVP		0.64
MPC		0.54
ClinPred		0.19	T
GERP RS		4.4
Varity_R		0.092
gMVP		0.51
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs370547479; hg19: chr9-137676847;