NM_000093.5:c.4135C>T

Variant names:

• chr9-134817038-C-T
• rs61739195
• NM_000093.5:c.4135C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.4135C>T​(p.Pro1379Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00768 in 1,613,868 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 34)
  • Exomes 𝑓: 0.0079 (72 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.85
• Publications: 20 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000093.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.012166917).
• BP6: Variant 9-134817038-C-T is Benign according to our data. Variant chr9-134817038-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00603 (919/152342) while in subpopulation NFE AF = 0.00883 (601/68036). AF 95% confidence interval is 0.00825. There are 9 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 919 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.4135C>T	p.Pro1379Ser	missense	Exon 53 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4135C>T	p.Pro1379Ser	missense	Exon 53 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.4135C>T	p.Pro1379Ser	missense	Exon 53 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4135C>T	p.Pro1379Ser	missense	Exon 53 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4126C>T	p.Pro1376Ser	missense	Exon 53 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 921 AN: 152224 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00749 AC: 1882 AN: 251426 AF XY: 0.00787

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00674

Gnomad NFE exome AF: 0.00885

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00785 AC: 11478 AN: 1461526 Hom.: 72 Cov.: 32 AF XY: 0.00800 AC XY: 5816 AN XY: 727078

African (AFR) AF: 0.00125 AC: 42 AN: 33478

American (AMR) AF: 0.00496 AC: 222 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 640 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00752 AC: 649 AN: 86250

European-Finnish (FIN) AF: 0.00624 AC: 333 AN: 53358

Middle Eastern (MID) AF: 0.0295 AC: 170 AN: 5764

European-Non Finnish (NFE) AF: 0.00805 AC: 8945 AN: 1111742

Other (OTH) AF: 0.00788 AC: 476 AN: 60388

GnomAD4 genome AF: 0.00603 AC: 919 AN: 152342 Hom.: 9 Cov.: 34 AF XY: 0.00579 AC XY: 431 AN XY: 74498

African (AFR) AF: 0.00106 AC: 44 AN: 41572

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00883 AC: 601 AN: 68036

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00821 Hom.: 10

Bravo AF: 0.00526

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00741 AC: 900

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.00990

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (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	Uncertain	0.56
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.012	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.86
MPC		0.30
ClinPred		0.013	T
GERP RS		5.0
Varity_R		0.38
gMVP		0.29
Mutation Taster		=77/23	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: rs61739195; hg19: chr9-137708884; COSMIC: COSV99057202;