rs145134399

Positions:

• chr9-134809281-C-A
• chr9-134809281-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000093.5(COL5A1):​c.3465C>A​(p.Asp1155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1155D) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3861127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3465C>A	p.Asp1155Glu	missense_variant	43/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3465C>A	p.Asp1155Glu	missense_variant	43/66		NP_001265003.1
COL5A1	XM_017014266.3	c.3465C>A	p.Asp1155Glu	missense_variant	43/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3465C>A	p.Asp1155Glu	missense_variant	43/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3465C>A	p.Asp1155Glu	missense_variant	43/66	2		ENSP00000360885.4
COL5A1	ENST00000463925.1	n.321C>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	0.015
DANN	Benign	0.76
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.61	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.49
Sift	Benign	0.14	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.99	D;.
Vest4		0.56
MutPred		0.25		Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);
MVP		0.74
MPC		0.50
ClinPred		0.81	D
GERP RS		-5.2
Varity_R		0.18
gMVP		0.27

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: rs145134399; hg19: chr9-137701127;