9-134810213-G-C

Variant names:

• chr9-134810213-G-C
• rs3811152
• NM_000093.5:c.3475-42G>C

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.3475-42G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,607,744 control chromosomes in the GnomAD database, including 19,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5975 hom., cov: 34)
  • Exomes 𝑓: 0.12 (13145 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00800
• 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, PanelApp Australia, Genomics England PanelApp, Ambry Genetics
• 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=-0.85).
• BP6: Variant 9-134810213-G-C is Benign according to our data. Variant chr9-134810213-G-C is described in ClinVar as Benign. ClinVar VariationId is 255078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 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.3475-42G>C		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.3475-42G>C		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.3475-42G>C		intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.3475-42G>C		intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.3466-42G>C		intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32967 AN: 152124 Hom.: 5950 Cov.: 34

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0887

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.135 AC: 33843 AN: 250972 AF XY: 0.129

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.0978

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0923

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.118 AC: 171973 AN: 1455502 Hom.: 13145 Cov.: 30 AF XY: 0.117 AC XY: 84910 AN XY: 724490

African (AFR) AF: 0.514 AC: 17151 AN: 33340

American (AMR) AF: 0.105 AC: 4681 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3390 AN: 26098

East Asian (EAS) AF: 0.115 AC: 4552 AN: 39658

South Asian (SAS) AF: 0.125 AC: 10728 AN: 86128

European-Finnish (FIN) AF: 0.0906 AC: 4833 AN: 53364

Middle Eastern (MID) AF: 0.163 AC: 939 AN: 5752

European-Non Finnish (NFE) AF: 0.106 AC: 117300 AN: 1106308

Other (OTH) AF: 0.140 AC: 8399 AN: 60142

GnomAD4 genome AF: 0.217 AC: 33039 AN: 152242 Hom.: 5975 Cov.: 34 AF XY: 0.211 AC XY: 15729 AN XY: 74430

African (AFR) AF: 0.500 AC: 20758 AN: 41516

American (AMR) AF: 0.131 AC: 1998 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 450 AN: 3470

East Asian (EAS) AF: 0.116 AC: 601 AN: 5180

South Asian (SAS) AF: 0.135 AC: 652 AN: 4822

European-Finnish (FIN) AF: 0.0887 AC: 942 AN: 10618

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7101 AN: 68016

Other (OTH) AF: 0.198 AC: 418 AN: 2116

Alfa AF: 0.0925 Hom.: 241

Bravo AF: 0.232

Asia WGS AF: 0.181 AC: 630 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	-0.85
CADD	Benign	4.1
DANN	Benign	0.37
PhyloP100		-0.0080
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: rs3811152; hg19: chr9-137702059; COSMIC: COSV65667215;