9-134728628-C-T

Variant names:

• chr9-134728628-C-T
• rs3124302
• NM_000093.5:c.787-42C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.787-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,611,774 control chromosomes in the GnomAD database, including 163,584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13446 hom., cov: 33)
  • Exomes 𝑓: 0.45 (150138 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.41
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-134728628-C-T is Benign according to our data. Variant chr9-134728628-C-T is described in ClinVar as Benign. ClinVar VariationId is 255100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.787-42C>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.787-42C>T		intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.787-42C>T		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.787-42C>T		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60927 AN: 151930 Hom.: 13429 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.480 AC: 120009 AN: 250212 AF XY: 0.476

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.709

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.443

Gnomad OTH exome AF: 0.489

GnomAD4 exome AF: 0.448 AC: 654597 AN: 1459726 Hom.: 150138 Cov.: 38 AF XY: 0.449 AC XY: 326277 AN XY: 726224

African (AFR) AF: 0.207 AC: 6922 AN: 33458

American (AMR) AF: 0.694 AC: 31022 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 16407 AN: 26128

East Asian (EAS) AF: 0.470 AC: 18659 AN: 39684

South Asian (SAS) AF: 0.471 AC: 40582 AN: 86228

European-Finnish (FIN) AF: 0.463 AC: 24239 AN: 52330

Middle Eastern (MID) AF: 0.494 AC: 2843 AN: 5758

European-Non Finnish (NFE) AF: 0.438 AC: 486493 AN: 1111064

Other (OTH) AF: 0.454 AC: 27430 AN: 60358

GnomAD4 genome AF: 0.401 AC: 60979 AN: 152048 Hom.: 13446 Cov.: 33 AF XY: 0.409 AC XY: 30399 AN XY: 74300

African (AFR) AF: 0.220 AC: 9139 AN: 41492

American (AMR) AF: 0.576 AC: 8811 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2168 AN: 3466

East Asian (EAS) AF: 0.481 AC: 2468 AN: 5136

South Asian (SAS) AF: 0.468 AC: 2249 AN: 4808

European-Finnish (FIN) AF: 0.462 AC: 4893 AN: 10580

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29854 AN: 67950

Other (OTH) AF: 0.453 AC: 959 AN: 2116

Alfa AF: 0.434 Hom.: 2891

Bravo AF: 0.402

Asia WGS AF: 0.509 AC: 1764 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.046
DANN	Benign	0.91
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3124302; hg19: chr9-137620474; COSMIC: COSV65677079; COSMIC: COSV65677079;