rs863223460

Variant names:

• chr9-134823423-C-G
• rs863223460
• NM_000093.5:c.4652C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-134823423-C-G
• chr9-134823423-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000093.5(COL5A1):​c.4652C>G​(p.Thr1551Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1551P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03
• Publications: 2 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: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• 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

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28485936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4652C>G	p.Thr1551Ser	missense_variant	Exon 61 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4652C>G	p.Thr1551Ser	missense_variant	Exon 61 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4652C>G	p.Thr1551Ser	missense_variant	Exon 61 of 65		XP_016869755.1
LOC101448202	NR_103451.2	n.71-3214G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4652C>G	p.Thr1551Ser	missense_variant	Exon 61 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4652C>G	p.Thr1551Ser	missense_variant	Exon 61 of 66	2		ENSP00000360885.4
COL5A1	ENST00000460264.5	n.120C>G		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 17, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with COL5A1-related conditions. This sequence change replaces threonine with serine at codon 1551 of the COL5A1 protein (p.Thr1551Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.00078	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.024
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.32	N;N
PhyloP100		6.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.77	N;.
REVEL	Benign	0.28
Sift	Benign	0.25	T;.
Sift4G	Benign	0.43	T;T
Polyphen		0.0030	B;.
Vest4		0.29
MutPred		0.31		Gain of glycosylation at T1551 (P = 0.1589);Gain of glycosylation at T1551 (P = 0.1589);
MVP		0.44
MPC		0.27
ClinPred		0.79	D
GERP RS		4.2
Varity_R		0.087
gMVP		0.22
Mutation Taster		=64/36	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: rs863223460; hg19: chr9-137715269;