rs112600748

Variant names:

• chr9-134825924-C-G
• rs112600748
• NM_000093.5:c.5067+20C>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.5067+20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,548,826 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (56 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (60 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.97
• Publications: 2 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

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 9-134825924-C-G is Benign according to our data. Variant chr9-134825924-C-G is described in ClinVar as Benign. ClinVar VariationId is 136907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 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.5067+20C>G		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.5067+20C>G		intron	N/A	NP_001265003.1
	LOC101448202	NR_103451.2		n.71-5715G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.5067+20C>G		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.5067+20C>G		intron	N/A	ENSP00000360885.4
	COL5A1	ENST00000460264.5	TSL:3	n.535+20C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2381 AN: 152234 Hom.: 55 Cov.: 34

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00441 AC: 1106 AN: 250642 AF XY: 0.00310

Gnomad AFR exome AF: 0.0549

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00179 AC: 2494 AN: 1396474 Hom.: 60 Cov.: 22 AF XY: 0.00153 AC XY: 1070 AN XY: 698310

African (AFR) AF: 0.0542 AC: 1744 AN: 32188

American (AMR) AF: 0.00503 AC: 224 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39230

South Asian (SAS) AF: 0.0000826 AC: 7 AN: 84732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53072

Middle Eastern (MID) AF: 0.00608 AC: 34 AN: 5594

European-Non Finnish (NFE) AF: 0.000231 AC: 243 AN: 1053242

Other (OTH) AF: 0.00416 AC: 242 AN: 58226

GnomAD4 genome AF: 0.0157 AC: 2389 AN: 152352 Hom.: 56 Cov.: 34 AF XY: 0.0146 AC XY: 1089 AN XY: 74494

African (AFR) AF: 0.0541 AC: 2249 AN: 41572

American (AMR) AF: 0.00503 AC: 77 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68040

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00735 Hom.: 5

Bravo AF: 0.0174

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.072
DANN	Benign	0.43
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs112600748; hg19: chr9-137717770;