9-134798472-A-T

Variant names:

• chr9-134798472-A-T
• rs4240707
• NM_000093.5:c.2952+11A>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.2952+11A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,612,640 control chromosomes in the GnomAD database, including 207,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20544 hom., cov: 33)
  • Exomes 𝑓: 0.50 (187268 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.10
• Publications: 13 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=-0.87).
• BP6: Variant 9-134798472-A-T is Benign according to our data. Variant chr9-134798472-A-T is described in ClinVar as Benign. ClinVar VariationId is 136877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

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.2952+11A>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.2952+11A>T		intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.2952+11A>T		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.2952+11A>T		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78460 AN: 151978 Hom.: 20542 Cov.: 33

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.509

GnomAD2 exomes AF: 0.520 AC: 130255 AN: 250676 AF XY: 0.518

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.540

Gnomad EAS exome AF: 0.785

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.492

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.503 AC: 734686 AN: 1460544 Hom.: 187268 Cov.: 38 AF XY: 0.504 AC XY: 366347 AN XY: 726668

African (AFR) AF: 0.556 AC: 18618 AN: 33458

American (AMR) AF: 0.466 AC: 20841 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 13970 AN: 26134

East Asian (EAS) AF: 0.764 AC: 30311 AN: 39694

South Asian (SAS) AF: 0.533 AC: 45917 AN: 86220

European-Finnish (FIN) AF: 0.457 AC: 24394 AN: 53364

Middle Eastern (MID) AF: 0.546 AC: 3147 AN: 5768

European-Non Finnish (NFE) AF: 0.492 AC: 546340 AN: 1110860

Other (OTH) AF: 0.516 AC: 31148 AN: 60340

GnomAD4 genome AF: 0.516 AC: 78506 AN: 152096 Hom.: 20544 Cov.: 33 AF XY: 0.514 AC XY: 38208 AN XY: 74332

African (AFR) AF: 0.558 AC: 23163 AN: 41500

American (AMR) AF: 0.448 AC: 6843 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1866 AN: 3468

East Asian (EAS) AF: 0.774 AC: 3990 AN: 5158

South Asian (SAS) AF: 0.539 AC: 2605 AN: 4830

European-Finnish (FIN) AF: 0.458 AC: 4843 AN: 10576

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33697 AN: 67972

Other (OTH) AF: 0.510 AC: 1077 AN: 2112

Alfa AF: 0.510 Hom.: 3612

Bravo AF: 0.518

Asia WGS AF: 0.646 AC: 2243 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 10, 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: The COL5A1 c.2952+11A>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 63233/120718 control chromosomes at a frequency of 0.5238076, which is approximately 419046 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is 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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.77
DANN	Benign	0.35
PhyloP100		-1.1
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: rs4240707; hg19: chr9-137690318;