chr9-134835182-G-C

Variant names:

• chr9-134835182-G-C
• NM_000093.5:c.5348G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000093.5(COL5A1):​c.5348G>C​(p.Arg1783Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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]

LOC101448202 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5348G>C	p.Arg1783Pro	missense_variant	Exon 65 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5348G>C	p.Arg1783Pro	missense_variant	Exon 65 of 66		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14973C>G		intron_variant	Intron 1 of 1
COL5A1	XM_017014266.3	c.*2429G>C		downstream_gene_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5348G>C	p.Arg1783Pro	missense_variant	Exon 65 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5348G>C	p.Arg1783Pro	missense_variant	Exon 65 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1783 of the COL5A1 protein (p.Arg1783Pro). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL5A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.031	D;D
Polyphen		0.74	P;.
Vest4		0.80
MutPred		0.68		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.91
MPC		0.42
ClinPred		0.91	D
GERP RS		1.1
Varity_R		0.94
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-137727028;