rs3124932

Variant names:

• chr9-134780166-C-T
• rs3124932
• NM_000093.5:c.2430+20C>T

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.2430+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,611,542 control chromosomes in the GnomAD database, including 163,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12189 hom., cov: 33)
  • Exomes 𝑓: 0.45 (151569 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.76
• Publications: 10 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=-0.96).
• BP6: Variant 9-134780166-C-T is Benign according to our data. Variant chr9-134780166-C-T is described in ClinVar as Benign. ClinVar VariationId is 136866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 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.2430+20C>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.2430+20C>T		intron	N/A	NP_001265003.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.2430+20C>T		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.2430+20C>T		intron	N/A	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.2421+20C>T		intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55888 AN: 151986 Hom.: 12184 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.0810

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.401

GnomAD2 exomes AF: 0.418 AC: 104628 AN: 250528 AF XY: 0.426

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.0660

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.461

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.447 AC: 651994 AN: 1459438 Hom.: 151569 Cov.: 39 AF XY: 0.448 AC XY: 325358 AN XY: 726128

African (AFR) AF: 0.137 AC: 4583 AN: 33464

American (AMR) AF: 0.485 AC: 21669 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 13069 AN: 26116

East Asian (EAS) AF: 0.0743 AC: 2951 AN: 39700

South Asian (SAS) AF: 0.459 AC: 39546 AN: 86240

European-Finnish (FIN) AF: 0.489 AC: 25622 AN: 52360

Middle Eastern (MID) AF: 0.454 AC: 2619 AN: 5764

European-Non Finnish (NFE) AF: 0.465 AC: 516356 AN: 1110742

Other (OTH) AF: 0.424 AC: 25579 AN: 60340

GnomAD4 genome AF: 0.368 AC: 55900 AN: 152104 Hom.: 12189 Cov.: 33 AF XY: 0.371 AC XY: 27607 AN XY: 74340

African (AFR) AF: 0.148 AC: 6143 AN: 41516

American (AMR) AF: 0.487 AC: 7433 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1718 AN: 3472

East Asian (EAS) AF: 0.0803 AC: 414 AN: 5158

South Asian (SAS) AF: 0.452 AC: 2182 AN: 4826

European-Finnish (FIN) AF: 0.489 AC: 5178 AN: 10588

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31251 AN: 67954

Other (OTH) AF: 0.406 AC: 857 AN: 2110

Alfa AF: 0.436 Hom.: 29178

Bravo AF: 0.358

Asia WGS AF: 0.275 AC: 956 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.040
DANN	Benign	0.58
PhyloP100		-1.8
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: rs3124932; hg19: chr9-137672012; COSMIC: COSV65666833;