9-134817127-A-G

Variant names:

• chr9-134817127-A-G
• rs10858283
• NM_000093.5:c.4176+48A>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.4176+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,550,680 control chromosomes in the GnomAD database, including 138,602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17322 hom., cov: 33)
  • Exomes 𝑓: 0.41 (121280 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27
• Publications: 7 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 9-134817127-A-G is Benign according to our data. Variant chr9-134817127-A-G is described in ClinVar as Benign. ClinVar VariationId is 255086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.616 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.4176+48A>G		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.4176+48A>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.4176+48A>G		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.4176+48A>G		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70824 AN: 151782 Hom.: 17296 Cov.: 33

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.416 AC: 102242 AN: 246056 AF XY: 0.409

Gnomad AFR exome AF: 0.631

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.414 AC: 578778 AN: 1398780 Hom.: 121280 Cov.: 24 AF XY: 0.412 AC XY: 288278 AN XY: 699394

African (AFR) AF: 0.632 AC: 20540 AN: 32512

American (AMR) AF: 0.375 AC: 16581 AN: 44196

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9463 AN: 25656

East Asian (EAS) AF: 0.451 AC: 17761 AN: 39340

South Asian (SAS) AF: 0.352 AC: 29905 AN: 84924

European-Finnish (FIN) AF: 0.360 AC: 19048 AN: 52872

Middle Eastern (MID) AF: 0.441 AC: 2276 AN: 5164

European-Non Finnish (NFE) AF: 0.416 AC: 438733 AN: 1055830

Other (OTH) AF: 0.420 AC: 24471 AN: 58286

GnomAD4 genome AF: 0.467 AC: 70902 AN: 151900 Hom.: 17322 Cov.: 33 AF XY: 0.460 AC XY: 34126 AN XY: 74260

African (AFR) AF: 0.622 AC: 25780 AN: 41414

American (AMR) AF: 0.394 AC: 6017 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3464

East Asian (EAS) AF: 0.459 AC: 2364 AN: 5150

South Asian (SAS) AF: 0.338 AC: 1625 AN: 4804

European-Finnish (FIN) AF: 0.364 AC: 3848 AN: 10568

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

European-Non Finnish (NFE) AF: 0.421 AC: 28559 AN: 67908

Other (OTH) AF: 0.450 AC: 952 AN: 2114

Alfa AF: 0.446 Hom.: 2869

Bravo AF: 0.479

Asia WGS AF: 0.401 AC: 1399 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	0.54
DANN	Benign	0.37
PhyloP100		-1.3
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: rs10858283; hg19: chr9-137708973; COSMIC: COSV65666842;