9-134642193-C-G

Position:

• chr9-134642193-C-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.6C>G​(p.Asp2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,134,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.126

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=0.3766986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.6C>G	p.Asp2Glu	missense_variant	1/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.6C>G	p.Asp2Glu	missense_variant	1/66		NP_001265003.1
COL5A1	XM_017014266.3	c.6C>G	p.Asp2Glu	missense_variant	1/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.6C>G	p.Asp2Glu	missense_variant	1/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.6C>G	p.Asp2Glu	missense_variant	1/66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1134564 Hom.: 0 Cov.: 31 AF XY: 0.00000182 AC XY: 1 AN XY: 548686

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: 0.00

Gnomad4 NFE exome AF: 0.00000211

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2017

A variant of uncertain significance has been identified in the COL5A1 gene. The D2E variant has not been published as pathogenic or been reported as benign to our knowledge. No data are available from control populations to assess the frequency of this variant. However, the D2E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is only conserved in mammals and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the D2E variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.53	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.60	N;.
REVEL	Benign	0.25
Sift	Benign	0.46	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.75	P;.
Vest4		0.13
MutPred		0.24		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.66
MPC		0.60
ClinPred		0.47	T
GERP RS		1.8
Varity_R		0.064
gMVP		0.26

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: rs1064796482; hg19: chr9-137534039;