rs147398633

Variant names:

• chr9-134823032-C-G
• NM_000093.5:c.4643C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-134823032-C-G
• chr9-134823032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000093.5(COL5A1):​c.4643C>G​(p.Ser1548Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Scores: Splicing: ADA: 0.9827
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4643C>G	p.Ser1548Trp	missense_variant	Exon 60 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4643C>G	p.Ser1548Trp	missense_variant	Exon 60 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4643C>G	p.Ser1548Trp	missense_variant	Exon 60 of 65		XP_016869755.1
LOC101448202	NR_103451.2	n.71-2823G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4643C>G	p.Ser1548Trp	missense_variant	Exon 60 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4643C>G	p.Ser1548Trp	missense_variant	Exon 60 of 66	2		ENSP00000360885.4
COL5A1	ENST00000460264.5	n.111C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Jun 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 1548 of the COL5A1 protein (p.Ser1548Trp). 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. 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.55
MutPred		0.37		Loss of phosphorylation at S1548 (P = 0.0028);Loss of phosphorylation at S1548 (P = 0.0028);
MVP		0.69
MPC		0.40
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.020		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: chr9-137714878;