9-134820151-G-C

Variant names:

• chr9-134820151-G-C
• rs2228560
• NM_000093.5:c.4482G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):​c.4482G>C​(p.Pro1494Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,613,406 control chromosomes in the GnomAD database, including 109,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1494P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (12196 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97508 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.64
• Publications: 18 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-134820151-G-C is Benign according to our data. Variant chr9-134820151-G-C is described in ClinVar as Benign. ClinVar VariationId is 136900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 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.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.129C>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4473G>C	p.Pro1491Pro	synonymous	Exon 58 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59875 AN: 152034 Hom.: 12172 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.369 AC: 92653 AN: 251342 AF XY: 0.368

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.314

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.385

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.363 AC: 530889 AN: 1461254 Hom.: 97508 Cov.: 47 AF XY: 0.364 AC XY: 264673 AN XY: 726936

African (AFR) AF: 0.505 AC: 16890 AN: 33470

American (AMR) AF: 0.313 AC: 14010 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9014 AN: 26132

East Asian (EAS) AF: 0.376 AC: 14938 AN: 39686

South Asian (SAS) AF: 0.380 AC: 32819 AN: 86254

European-Finnish (FIN) AF: 0.350 AC: 18657 AN: 53246

Middle Eastern (MID) AF: 0.422 AC: 2435 AN: 5764

European-Non Finnish (NFE) AF: 0.360 AC: 399990 AN: 1111604

Other (OTH) AF: 0.367 AC: 22136 AN: 60380

GnomAD4 genome AF: 0.394 AC: 59941 AN: 152152 Hom.: 12196 Cov.: 33 AF XY: 0.387 AC XY: 28790 AN XY: 74376

African (AFR) AF: 0.495 AC: 20557 AN: 41524

American (AMR) AF: 0.316 AC: 4826 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3472

East Asian (EAS) AF: 0.379 AC: 1955 AN: 5164

South Asian (SAS) AF: 0.367 AC: 1771 AN: 4828

European-Finnish (FIN) AF: 0.341 AC: 3618 AN: 10606

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24797 AN: 67968

Other (OTH) AF: 0.384 AC: 810 AN: 2112

Alfa AF: 0.0297 Hom.: 271

EpiCase AF: 0.358

EpiControl AF: 0.356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.048
DANN	Benign	0.55
PhyloP100		-4.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228560; hg19: chr9-137711997; COSMIC: COSV65668786; COSMIC: COSV65668786;