rs863223479

Positions:

• chr9-134817078-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000093.5(COL5A1):​c.4175G>A​(p.Arg1392Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Scores: Splicing: ADA: 0.8312
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -3 ACMG points.

• 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.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4175G>A	p.Arg1392Lys	missense_variant, splice_region_variant	53/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4175G>A	p.Arg1392Lys	missense_variant, splice_region_variant	53/66		NP_001265003.1
COL5A1	XM_017014266.3	c.4175G>A	p.Arg1392Lys	missense_variant, splice_region_variant	53/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4175G>A	p.Arg1392Lys	missense_variant, splice_region_variant	53/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4175G>A	p.Arg1392Lys	missense_variant, splice_region_variant	53/66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461054 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2020

The p.R1392K variant (also known as c.4175G>A), located in coding exon 53 of the COL5A1 gene, results from a G to A substitution at nucleotide position 4175. The arginine at codon 1392 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2020

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213052; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Symoens et al., 2012; Stenson et al., 2014) -

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1392 of the COL5A1 protein (p.Arg1392Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 213052). 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.1	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.056	T;T
Polyphen		0.96	P;.
Vest4		0.52
MutPred		0.36		Gain of glycosylation at R1392 (P = 0.0042);Gain of glycosylation at R1392 (P = 0.0042);
MVP		0.80
MPC		0.30
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.61
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.67
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: rs863223479; hg19: chr9-137708924; COSMIC: COSV65665394;