rs770173348

Variant names:

• chr9-134728805-G-A
• rs770173348
• NM_000093.5:c.922G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134728805-G-A
• chr9-134728805-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000093.5(COL5A1):​c.922G>A​(p.Glu308Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002072
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25193596).
• BS2: High AC in GnomAdExome4 at 15 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.922G>A	p.Glu308Lys	missense splice_region	Exon 6 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.922G>A	p.Glu308Lys	missense splice_region	Exon 6 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.922G>A	p.Glu308Lys	missense splice_region	Exon 6 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.922G>A	p.Glu308Lys	missense splice_region	Exon 6 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.915+7G>A		splice_region intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250060 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461768 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727182

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.33
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.84	P
Vest4		0.40
MutPred		0.32		Gain of ubiquitination at E308 (P = 0.0022)
MVP		0.62
MPC		0.22
ClinPred		0.20	T
GERP RS		3.4
Varity_R		0.055
gMVP		0.27
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0080
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: rs770173348; hg19: chr9-137620651; COSMIC: COSV65672484; COSMIC: COSV65672484;