rs148648778

Variant names:

• chr9-134782675-C-T
• rs148648778
• NM_000093.5:c.2439C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.2439C>T​(p.Asp813Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000966 in 1,613,578 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (4 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.820
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 9-134782675-C-T is Benign according to our data. Variant chr9-134782675-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00326 (496/152056) while in subpopulation AFR AF = 0.00948 (393/41456). AF 95% confidence interval is 0.00871. There are 5 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 496 AD gene.

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.2439C>T	p.Asp813Asp	synonymous	Exon 29 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.2439C>T	p.Asp813Asp	synonymous	Exon 29 of 66	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.2439C>T	p.Asp813Asp	synonymous	Exon 29 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2439C>T	p.Asp813Asp	synonymous	Exon 29 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2430C>T	p.Asp810Asp	synonymous	Exon 29 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 151940 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00944

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00134 AC: 337 AN: 251290 AF XY: 0.00107

Gnomad AFR exome AF: 0.00985

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00283

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000727 AC: 1063 AN: 1461522 Hom.: 4 Cov.: 32 AF XY: 0.000722 AC XY: 525 AN XY: 727036

African (AFR) AF: 0.0108 AC: 363 AN: 33474

American (AMR) AF: 0.000783 AC: 35 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00164 AC: 65 AN: 39686

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86254

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53296

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000465 AC: 517 AN: 1111830

Other (OTH) AF: 0.000928 AC: 56 AN: 60372

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152056 Hom.: 5 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74332

African (AFR) AF: 0.00948 AC: 393 AN: 41456

American (AMR) AF: 0.00131 AC: 20 AN: 15288

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

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5158

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00173 Hom.: 2

Bravo AF: 0.00357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal (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	-0.27
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-0.82
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs148648778; hg19: chr9-137674521;