NM_000093.5:c.1432-5T>C

Variant names:

• chr9-134738741-T-C
• rs3128612
• NM_000093.5:c.1432-5T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.1432-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 1,606,282 control chromosomes in the GnomAD database, including 215,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25614 hom., cov: 33)
  • Exomes 𝑓: 0.50 (189520 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Scores: Splicing: ADA: 0.04311
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.130
• Publications: 16 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-134738741-T-C is Benign according to our data. Variant chr9-134738741-T-C is described in ClinVar as Benign. ClinVar VariationId is 136931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.1432-5T>C		splice_region intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.1432-5T>C		splice_region intron	N/A	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.1432-5T>C		splice_region intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.1432-5T>C		splice_region intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.1423-5T>C		splice_region intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85560 AN: 151886 Hom.: 25585 Cov.: 33

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.481 AC: 120732 AN: 250958 AF XY: 0.482

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.522

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.509

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.505 AC: 734045 AN: 1454276 Hom.: 189520 Cov.: 34 AF XY: 0.503 AC XY: 364440 AN XY: 723930

African (AFR) AF: 0.790 AC: 26315 AN: 33326

American (AMR) AF: 0.267 AC: 11919 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8520 AN: 26082

East Asian (EAS) AF: 0.519 AC: 20568 AN: 39656

South Asian (SAS) AF: 0.484 AC: 41661 AN: 86064

European-Finnish (FIN) AF: 0.506 AC: 26982 AN: 53360

Middle Eastern (MID) AF: 0.451 AC: 2594 AN: 5754

European-Non Finnish (NFE) AF: 0.512 AC: 565381 AN: 1105156

Other (OTH) AF: 0.500 AC: 30105 AN: 60204

GnomAD4 genome AF: 0.563 AC: 85636 AN: 152006 Hom.: 25614 Cov.: 33 AF XY: 0.555 AC XY: 41258 AN XY: 74284

African (AFR) AF: 0.774 AC: 32087 AN: 41468

American (AMR) AF: 0.370 AC: 5664 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2590 AN: 5132

South Asian (SAS) AF: 0.482 AC: 2325 AN: 4824

European-Finnish (FIN) AF: 0.503 AC: 5323 AN: 10578

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34707 AN: 67926

Other (OTH) AF: 0.497 AC: 1051 AN: 2116

Alfa AF: 0.517 Hom.: 14730

Bravo AF: 0.562

Asia WGS AF: 0.467 AC: 1630 AN: 3478

EpiCase AF: 0.496

EpiControl AF: 0.495

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		0.13
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.043
dbscSNV1_RF	Benign	0.11
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: rs3128612; hg19: chr9-137630587; COSMIC: COSV65665294;