9-134796811-A-G

Variant names:

• chr9-134796811-A-G
• rs3811159
• NM_000093.5:c.2845-37A>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.2845-37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,600,080 control chromosomes in the GnomAD database, including 177,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18434 hom., cov: 33)
  • Exomes 𝑓: 0.46 (158759 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.300
• 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=-0.98).
• BP6: Variant 9-134796811-A-G is Benign according to our data. Variant chr9-134796811-A-G is described in ClinVar as Benign. ClinVar VariationId is 255072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 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.2845-37A>G		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.2845-37A>G		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.2845-37A>G		intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2845-37A>G		intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2836-37A>G		intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74000 AN: 151858 Hom.: 18424 Cov.: 33

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.474

GnomAD2 exomes AF: 0.482 AC: 120722 AN: 250660 AF XY: 0.477

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.498

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.452

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.465 AC: 672713 AN: 1448104 Hom.: 158759 Cov.: 31 AF XY: 0.465 AC XY: 335299 AN XY: 721446

African (AFR) AF: 0.551 AC: 18325 AN: 33232

American (AMR) AF: 0.446 AC: 19941 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 12810 AN: 26042

East Asian (EAS) AF: 0.715 AC: 28328 AN: 39634

South Asian (SAS) AF: 0.467 AC: 40138 AN: 85962

European-Finnish (FIN) AF: 0.417 AC: 22197 AN: 53288

Middle Eastern (MID) AF: 0.507 AC: 2911 AN: 5742

European-Non Finnish (NFE) AF: 0.454 AC: 499467 AN: 1099618

Other (OTH) AF: 0.477 AC: 28596 AN: 59906

GnomAD4 genome AF: 0.487 AC: 74055 AN: 151976 Hom.: 18434 Cov.: 33 AF XY: 0.485 AC XY: 35999 AN XY: 74276

African (AFR) AF: 0.554 AC: 22981 AN: 41450

American (AMR) AF: 0.423 AC: 6461 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1728 AN: 3466

East Asian (EAS) AF: 0.741 AC: 3829 AN: 5164

South Asian (SAS) AF: 0.464 AC: 2235 AN: 4812

European-Finnish (FIN) AF: 0.417 AC: 4404 AN: 10560

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.458 AC: 31090 AN: 67942

Other (OTH) AF: 0.472 AC: 994 AN: 2108

Alfa AF: 0.467 Hom.: 65516

Bravo AF: 0.492

Asia WGS AF: 0.580 AC: 2014 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	-0.98
CADD	Benign	1.9
DANN	Benign	0.42
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs3811159; hg19: chr9-137688657; COSMIC: COSV65665298;