chr9-134754286-T-G

Position:

• chr9-134754286-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000093.5(COL5A1):​c.1787T>G​(p.Val596Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V596A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.16

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.1787T>G	p.Val596Gly	missense_variant	16/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.1787T>G	p.Val596Gly	missense_variant	16/66
COL5A1	XM_017014266.3	c.1787T>G	p.Val596Gly	missense_variant	16/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.1787T>G	p.Val596Gly	missense_variant	16/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.1787T>G	p.Val596Gly	missense_variant	16/66	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.79	D;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.48	T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.49	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.45
Sift	Benign	0.38	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.49	P;.
Vest4		0.39
MutPred		0.32		Gain of methylation at R594 (P = 0.0659);Gain of methylation at R594 (P = 0.0659);
MVP		0.79
MPC		1.7
ClinPred		0.88	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.58

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: rs754773665; hg19: chr9-137646132;