rs145178917

Variant names:

• chr9-134700009-G-T
• rs145178917
• NM_000093.5:c.378G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-134700009-G-T
• chr9-134700009-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.378G>T​(p.Gln126His) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,613,802 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (18 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 4.19
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012970805).
• BP6: Variant 9-134700009-G-T is Benign according to our data. Variant chr9-134700009-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00234 (357/152360) while in subpopulation EAS AF = 0.0324 (168/5178). AF 95% confidence interval is 0.0284. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 357 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.378G>T	p.Gln126His	missense	Exon 3 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.378G>T	p.Gln126His	missense	Exon 3 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.378G>T	p.Gln126His	missense	Exon 3 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.378G>T	p.Gln126His	missense	Exon 3 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.378G>T	p.Gln126His	missense	Exon 3 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152242 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0326

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00367 AC: 923 AN: 251178 AF XY: 0.00356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0320

Gnomad FIN exome AF: 0.00787

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00164 AC: 2399 AN: 1461442 Hom.: 18 Cov.: 32 AF XY: 0.00167 AC XY: 1217 AN XY: 726998

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

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.0342 AC: 1356 AN: 39700

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86258

European-Finnish (FIN) AF: 0.00723 AC: 383 AN: 52984

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000383 AC: 426 AN: 1112004

Other (OTH) AF: 0.00179 AC: 108 AN: 60390

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152360 Hom.: 4 Cov.: 32 AF XY: 0.00299 AC XY: 223 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.0324 AC: 168 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4820

European-Finnish (FIN) AF: 0.0105 AC: 112 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00201 Hom.: 12

Bravo AF: 0.00181

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00369 AC: 448

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		4.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.43		Gain of sheet (P = 0.1208)
MVP		0.82
MPC		0.62
ClinPred		0.10	T
GERP RS		2.9
Varity_R		0.46
gMVP		0.55
Mutation Taster		=85/15	polymorphism

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: rs145178917; hg19: chr9-137591855; COSMIC: COSV107479276;