NM_000093.5:c.925-49A>G

Variant names:

• chr9-134730187-A-G
• rs3124308
• NM_000093.5:c.925-49A>G

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.925-49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,602,426 control chromosomes in the GnomAD database, including 162,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13310 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149176 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.61
• Publications: 5 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=-0.96).
• BP6: Variant 9-134730187-A-G is Benign according to our data. Variant chr9-134730187-A-G is described in ClinVar as Benign. ClinVar VariationId is 255102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.564 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.925-49A>G		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.925-49A>G		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.925-49A>G		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.925-49A>G		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60643 AN: 151730 Hom.: 13293 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.479 AC: 116878 AN: 244116 AF XY: 0.475

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.626

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.448 AC: 649650 AN: 1450578 Hom.: 149176 Cov.: 39 AF XY: 0.449 AC XY: 323938 AN XY: 722004

African (AFR) AF: 0.206 AC: 6867 AN: 33366

American (AMR) AF: 0.693 AC: 30983 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 16388 AN: 26094

East Asian (EAS) AF: 0.471 AC: 18686 AN: 39678

South Asian (SAS) AF: 0.468 AC: 40306 AN: 86084

European-Finnish (FIN) AF: 0.463 AC: 21943 AN: 47418

Middle Eastern (MID) AF: 0.496 AC: 2506 AN: 5048

European-Non Finnish (NFE) AF: 0.437 AC: 484703 AN: 1108126

Other (OTH) AF: 0.454 AC: 27268 AN: 60072

GnomAD4 genome AF: 0.400 AC: 60695 AN: 151848 Hom.: 13310 Cov.: 33 AF XY: 0.408 AC XY: 30242 AN XY: 74198

African (AFR) AF: 0.219 AC: 9107 AN: 41500

American (AMR) AF: 0.574 AC: 8758 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2161 AN: 3458

East Asian (EAS) AF: 0.480 AC: 2455 AN: 5116

South Asian (SAS) AF: 0.464 AC: 2234 AN: 4818

European-Finnish (FIN) AF: 0.460 AC: 4846 AN: 10542

Middle Eastern (MID) AF: 0.452 AC: 131 AN: 290

European-Non Finnish (NFE) AF: 0.438 AC: 29745 AN: 67856

Other (OTH) AF: 0.453 AC: 956 AN: 2112

Alfa AF: 0.434 Hom.: 2882

Bravo AF: 0.402

Asia WGS AF: 0.507 AC: 1757 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	-0.96
CADD	Benign	0.60
DANN	Benign	0.48
PhyloP100		-1.6
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: rs3124308; hg19: chr9-137622033; COSMIC: COSV65673420; COSMIC: COSV65673420;