rs1060502262

Positions:

• chr9-134782700-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000093.5(COL5A1):​c.2464A>G​(p.Met822Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000662 in 151,020 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 Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39281043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2464A>G	p.Met822Val	missense_variant	29/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2464A>G	p.Met822Val	missense_variant	29/66		NP_001265003.1
COL5A1	XM_017014266.3	c.2464A>G	p.Met822Val	missense_variant	29/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2464A>G	p.Met822Val	missense_variant	29/66	1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.2464A>G	p.Met822Val	missense_variant	29/66	2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151020 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151020 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73726

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2018

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A1-related disease. This sequence change replaces methionine with valine at codon 822 of the COL5A1 protein (p.Met822Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	0.085	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.35
Sift	Benign	0.24	T;.
Sift4G	Benign	0.48	T;T
Polyphen		0.20	B;.
Vest4		0.39
MutPred		0.20		Loss of glycosylation at K819 (P = 0.1793);Loss of glycosylation at K819 (P = 0.1793);
MVP		0.72
MPC		0.55
ClinPred		0.90	D
GERP RS		4.2
Varity_R		0.39
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1060502262; hg19: chr9-137674546;