9-134738741-T-C

Variant names:

• chr9-134738741-T-C
• rs3128612
• NM_000093.5:c.1432-5T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.1432-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 1,606,282 control chromosomes in the GnomAD database, including 215,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25614 hom., cov: 33)
  • Exomes 𝑓: 0.50 (189520 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Scores: Splicing: ADA: 0.04311
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.130
• Publications: 16 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-134738741-T-C is Benign according to our data. Variant chr9-134738741-T-C is described in ClinVar as [Benign]. Clinvar id is 136931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1432-5T>C		splice_region_variant, intron_variant	Intron 10 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1432-5T>C		splice_region_variant, intron_variant	Intron 10 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.1432-5T>C		splice_region_variant, intron_variant	Intron 10 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1432-5T>C		splice_region_variant, intron_variant	Intron 10 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1432-5T>C		splice_region_variant, intron_variant	Intron 10 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85560 AN: 151886 Hom.: 25585 Cov.: 33

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.481 AC: 120732 AN: 250958 AF XY: 0.482

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.522

Gnomad FIN exome AF: 0.506

Gnomad NFE exome AF: 0.509

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.505 AC: 734045 AN: 1454276 Hom.: 189520 Cov.: 34 AF XY: 0.503 AC XY: 364440 AN XY: 723930

African (AFR) AF: 0.790 AC: 26315 AN: 33326

American (AMR) AF: 0.267 AC: 11919 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8520 AN: 26082

East Asian (EAS) AF: 0.519 AC: 20568 AN: 39656

South Asian (SAS) AF: 0.484 AC: 41661 AN: 86064

European-Finnish (FIN) AF: 0.506 AC: 26982 AN: 53360

Middle Eastern (MID) AF: 0.451 AC: 2594 AN: 5754

European-Non Finnish (NFE) AF: 0.512 AC: 565381 AN: 1105156

Other (OTH) AF: 0.500 AC: 30105 AN: 60204

GnomAD4 genome AF: 0.563 AC: 85636 AN: 152006 Hom.: 25614 Cov.: 33 AF XY: 0.555 AC XY: 41258 AN XY: 74284

African (AFR) AF: 0.774 AC: 32087 AN: 41468

American (AMR) AF: 0.370 AC: 5664 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3468

East Asian (EAS) AF: 0.505 AC: 2590 AN: 5132

South Asian (SAS) AF: 0.482 AC: 2325 AN: 4824

European-Finnish (FIN) AF: 0.503 AC: 5323 AN: 10578

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34707 AN: 67926

Other (OTH) AF: 0.497 AC: 1051 AN: 2116

Alfa AF: 0.517 Hom.: 14730

Bravo AF: 0.562

Asia WGS AF: 0.467 AC: 1630 AN: 3478

EpiCase AF: 0.496

EpiControl AF: 0.495

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 02, 2012

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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.1432-5T>C in COL5A1 gene is an intronic change that involves a conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.4997 (60614 / 121292chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00003 suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Benign/ Likely Benign by multiple reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

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

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Dec 29, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome type 7A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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	-0.41
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		0.13
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.043
dbscSNV1_RF	Benign	0.11
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: rs3128612; hg19: chr9-137630587; COSMIC: COSV65665294;