NM_000093.5:c.574G>A

Variant names:

• chr9-134701253-G-A
• rs138579182
• NM_000093.5:c.574G>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.574G>A​(p.Asp192Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,613,818 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D192E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (41 hom., cov: 33)
  • Exomes 𝑓: 0.020 (378 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.18
• Publications: 14 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 (MetaRNN=0.0070186555).
• BP6: Variant 9-134701253-G-A is Benign according to our data. Variant chr9-134701253-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136920.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 = 0.0155 (2362/152148) while in subpopulation NFE AF = 0.0223 (1519/68002). AF 95% confidence interval is 0.0214. There are 41 homozygotes in GnomAd4. There are 1222 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2362 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.574G>A	p.Asp192Asn	missense	Exon 4 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.574G>A	p.Asp192Asn	missense	Exon 4 of 66	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.574G>A	p.Asp192Asn	missense	Exon 4 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.574G>A	p.Asp192Asn	missense	Exon 4 of 66	ENSP00000360885.4
	COL5A1	ENST00000464187.1	TSL:2	n.996G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2361 AN: 152030 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00307

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0167 AC: 4170 AN: 250328 AF XY: 0.0167

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0198 AC: 28903 AN: 1461670 Hom.: 378 Cov.: 33 AF XY: 0.0195 AC XY: 14172 AN XY: 727112

African (AFR) AF: 0.00245 AC: 82 AN: 33480

American (AMR) AF: 0.00418 AC: 187 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 463 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00748 AC: 645 AN: 86252

European-Finnish (FIN) AF: 0.0470 AC: 2505 AN: 53272

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.0215 AC: 23875 AN: 1111966

Other (OTH) AF: 0.0187 AC: 1130 AN: 60390

GnomAD4 genome AF: 0.0155 AC: 2362 AN: 152148 Hom.: 41 Cov.: 33 AF XY: 0.0164 AC XY: 1222 AN XY: 74368

African (AFR) AF: 0.00306 AC: 127 AN: 41496

American (AMR) AF: 0.00569 AC: 87 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00706 AC: 34 AN: 4814

European-Finnish (FIN) AF: 0.0479 AC: 507 AN: 10582

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

European-Non Finnish (NFE) AF: 0.0223 AC: 1519 AN: 68002

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0181 Hom.: 69

Bravo AF: 0.0115

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0167 AC: 2022

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0160

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type (2)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (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	Benign	0.080
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.58	N
PhyloP100		2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.057
Sift	Benign	0.55	T
Sift4G	Benign	0.49	T
Polyphen		0.031	B
Vest4		0.072
MPC		0.21
ClinPred		0.0087	T
GERP RS		3.2
Varity_R		0.036
gMVP		0.22
Mutation Taster		=98/2	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: rs138579182; hg19: chr9-137593099; COSMIC: COSV106111098;