rs73558067

Variant names:

• chr9-134753816-C-T
• rs73558067
• NM_000093.5:c.1720-34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.1720-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,565,750 control chromosomes in the GnomAD database, including 41,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3527 hom., cov: 28)
  • Exomes 𝑓: 0.22 (37700 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.14
• Publications: 5 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 (BayesDel_noAF=-0.91).
• BP6: Variant 9-134753816-C-T is Benign according to our data. Variant chr9-134753816-C-T is described in ClinVar as Benign. ClinVar VariationId is 255054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1720-34C>T		intron_variant	Intron 14 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1720-34C>T		intron_variant	Intron 14 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.1720-34C>T		intron_variant	Intron 14 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1720-34C>T		intron_variant	Intron 14 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1720-34C>T		intron_variant	Intron 14 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31456 AN: 150336 Hom.: 3526 Cov.: 28

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.210 AC: 52572 AN: 249872 AF XY: 0.212

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.384

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.224 AC: 317155 AN: 1415296 Hom.: 37700 Cov.: 27 AF XY: 0.223 AC XY: 157338 AN XY: 706322

African (AFR) AF: 0.179 AC: 5835 AN: 32604

American (AMR) AF: 0.126 AC: 5610 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3530 AN: 25666

East Asian (EAS) AF: 0.377 AC: 14741 AN: 39102

South Asian (SAS) AF: 0.181 AC: 15432 AN: 85392

European-Finnish (FIN) AF: 0.221 AC: 11513 AN: 52014

Middle Eastern (MID) AF: 0.194 AC: 1018 AN: 5242

European-Non Finnish (NFE) AF: 0.230 AC: 246706 AN: 1072278

Other (OTH) AF: 0.218 AC: 12770 AN: 58600

GnomAD4 genome AF: 0.209 AC: 31447 AN: 150454 Hom.: 3527 Cov.: 28 AF XY: 0.207 AC XY: 15215 AN XY: 73390

African (AFR) AF: 0.177 AC: 7241 AN: 40884

American (AMR) AF: 0.161 AC: 2441 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 501 AN: 3464

East Asian (EAS) AF: 0.361 AC: 1814 AN: 5026

South Asian (SAS) AF: 0.171 AC: 803 AN: 4690

European-Finnish (FIN) AF: 0.218 AC: 2258 AN: 10364

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15561 AN: 67608

Other (OTH) AF: 0.204 AC: 421 AN: 2064

Alfa AF: 0.209 Hom.: 1439

Bravo AF: 0.209

Asia WGS AF: 0.216 AC: 750 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.29
DANN	Benign	0.56
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs73558067; hg19: chr9-137645662; COSMIC: COSV65670629;