9-134786460-G-T

Variant names:

• chr9-134786460-G-T
• rs3128621
• NM_000093.5:c.2646+412G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000093.5(COL5A1):​c.2646+412G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 152,046 control chromosomes in the GnomAD database, including 12,156 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (12156 hom., cov: 32)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.598
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.482 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.2646+412G>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.2646+412G>T		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.2646+412G>T		intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2646+412G>T		intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2637+412G>T		intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56042 AN: 151928 Hom.: 12153 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.403

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.369 AC: 56044 AN: 152046 Hom.: 12156 Cov.: 32 AF XY: 0.372 AC XY: 27648 AN XY: 74302

African (AFR) AF: 0.142 AC: 5890 AN: 41478

American (AMR) AF: 0.492 AC: 7515 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1709 AN: 3466

East Asian (EAS) AF: 0.153 AC: 789 AN: 5156

South Asian (SAS) AF: 0.467 AC: 2247 AN: 4810

European-Finnish (FIN) AF: 0.468 AC: 4944 AN: 10566

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31357 AN: 67970

Other (OTH) AF: 0.405 AC: 855 AN: 2110

Alfa AF: 0.445 Hom.: 26301

Bravo AF: 0.360

Asia WGS AF: 0.314 AC: 1092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.56
DANN	Benign	0.60
PhyloP100		-0.60
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: rs3128621; hg19: chr9-137678306;