9-134642248-C-T

Variant names:

• chr9-134642248-C-T
• rs548525119
• NM_000093.5:c.61C>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.61C>T​(p.Pro21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,280,862 control chromosomes in the GnomAD database, including 17 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. P21L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (15 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.802
• Publications: 7 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 -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 6 benign, 8 uncertain in NM_000093.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032570064).
• BP6: Variant 9-134642248-C-T is Benign according to our data. Variant chr9-134642248-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212930.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 = 0.00129 (195/150582) while in subpopulation EAS AF = 0.0301 (153/5082). AF 95% confidence interval is 0.0262. There are 2 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 195 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.61C>T	p.Pro21Ser	missense	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.61C>T	p.Pro21Ser	missense	Exon 1 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.61C>T	p.Pro21Ser	missense	Exon 1 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.61C>T	p.Pro21Ser	missense	Exon 1 of 66	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.61C>T	p.Pro21Ser	missense	Exon 1 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 196 AN: 150474 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.000999

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.00112 AC: 58 AN: 51914 AF XY: 0.00132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.000810

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00105 AC: 1191 AN: 1130280 Hom.: 15 Cov.: 27 AF XY: 0.00110 AC XY: 601 AN XY: 548624

African (AFR) AF: 0.00 AC: 0 AN: 23152

American (AMR) AF: 0.000173 AC: 3 AN: 17318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17572

East Asian (EAS) AF: 0.0341 AC: 809 AN: 23734

South Asian (SAS) AF: 0.00230 AC: 85 AN: 36986

European-Finnish (FIN) AF: 0.00135 AC: 32 AN: 23652

Middle Eastern (MID) AF: 0.000639 AC: 2 AN: 3128

European-Non Finnish (NFE) AF: 0.000155 AC: 146 AN: 940360

Other (OTH) AF: 0.00257 AC: 114 AN: 44378

GnomAD4 genome AF: 0.00129 AC: 195 AN: 150582 Hom.: 2 Cov.: 32 AF XY: 0.00143 AC XY: 105 AN XY: 73546

African (AFR) AF: 0.0000242 AC: 1 AN: 41320

American (AMR) AF: 0.000132 AC: 2 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.0301 AC: 153 AN: 5082

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.000999 AC: 10 AN: 10012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000178 AC: 12 AN: 67456

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.00142

ExAC AF: 0.00162 AC: 27

Asia WGS AF: 0.00973 AC: 32 AN: 3302

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome, classic type (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Connective tissue disorder (1)
-	-	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	Benign	0.078
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.3
DANN	Benign	0.97
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.80
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.16
Sift	Benign	0.91	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.25
MPC		0.15
ClinPred		0.012	T
GERP RS		-5.3
PromoterAI		-0.052	Neutral
Varity_R		0.022
gMVP		0.35
Mutation Taster		=91/9	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: rs548525119; hg19: chr9-137534094;