rs201375465

Variant names:

• chr9-134732126-C-A
• rs201375465
• NM_000093.5:c.1388C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134732126-C-A
• chr9-134732126-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000093.5(COL5A1):​c.1388C>A​(p.Pro463Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P463A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Scores: Splicing: ADA: 0.03823
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.13
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1388C>A	p.Pro463Gln	missense_variant, splice_region_variant	Exon 9 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1388C>A	p.Pro463Gln	missense_variant, splice_region_variant	Exon 9 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.1388C>A	p.Pro463Gln	missense_variant, splice_region_variant	Exon 9 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1388C>A	p.Pro463Gln	missense_variant, splice_region_variant	Exon 9 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1388C>A	p.Pro463Gln	missense_variant, splice_region_variant	Exon 9 of 66	2		ENSP00000360885.4
COL5A1	ENST00000469093.1	n.127C>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.13	T;.
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.32		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.80
MPC		0.62
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.63
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.26
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: rs201375465; hg19: chr9-137623972;