rs13297647

Variant names:

• chr9-134810219-A-C
• rs13297647
• NM_000093.5:c.3475-36A>C

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.3475-36A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,612,244 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (144 hom., cov: 34)
  • Exomes 𝑓: 0.049 (1917 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.104
• Publications: 1 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=-0.84).
• BP6: Variant 9-134810219-A-C is Benign according to our data. Variant chr9-134810219-A-C is described in ClinVar as Benign. ClinVar VariationId is 255077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3475-36A>C		intron_variant	Intron 43 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3475-36A>C		intron_variant	Intron 43 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.3475-36A>C		intron_variant	Intron 43 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3475-36A>C		intron_variant	Intron 43 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3475-36A>C		intron_variant	Intron 43 of 65	2		ENSP00000360885.4
COL5A1	ENST00000463925.1	n.331-36A>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5849 AN: 152256 Hom.: 144 Cov.: 34

Gnomad AFR AF: 0.00945

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0409 AC: 10269 AN: 251070 AF XY: 0.0411

Gnomad AFR exome AF: 0.00802

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0591

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0493 AC: 71950 AN: 1459870 Hom.: 1917 Cov.: 32 AF XY: 0.0486 AC XY: 35287 AN XY: 726394

African (AFR) AF: 0.00816 AC: 273 AN: 33444

American (AMR) AF: 0.0202 AC: 902 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 1067 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39694

South Asian (SAS) AF: 0.0171 AC: 1477 AN: 86222

European-Finnish (FIN) AF: 0.0707 AC: 3776 AN: 53374

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5766

European-Non Finnish (NFE) AF: 0.0555 AC: 61583 AN: 1110226

Other (OTH) AF: 0.0441 AC: 2661 AN: 60294

GnomAD4 genome AF: 0.0384 AC: 5848 AN: 152374 Hom.: 144 Cov.: 34 AF XY: 0.0382 AC XY: 2847 AN XY: 74520

African (AFR) AF: 0.00943 AC: 392 AN: 41588

American (AMR) AF: 0.0268 AC: 410 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4834

European-Finnish (FIN) AF: 0.0740 AC: 786 AN: 10624

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3896 AN: 68038

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0463 Hom.: 36

Bravo AF: 0.0344

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 15, 2022

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	-0.84
CADD	Benign	2.9
DANN	Benign	0.51
PhyloP100		0.10
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: rs13297647; hg19: chr9-137702065;