9-134834960-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):c.5137-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,600,592 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 7 hom. )

Consequence

COL5A1
NM_000093.5 intron

Scores

Splicing: ADA: 0.0002041

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.364

Publications

2 publications found

Variant links:

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

COL5A1 links:

LOC101448202 (HGNC:):

LOC101448202 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 9-134834960-T-C is Benign according to our data. Variant chr9-134834960-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00474 (722/152180) while in subpopulation AFR AF = 0.0162 (674/41524). AF 95% confidence interval is 0.0152. There are 8 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 722 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.5137-11T>C	intron_variant	Intron 64 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.5137-11T>C	intron_variant	Intron 64 of 65		NP_001265003.1
LOC101448202	NR_103451.2 link	n.71-14751A>G	intron_variant	Intron 1 of 1
COL5A1	XM_017014266.3 link	c.*2207T>C	downstream_gene_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.5137-11T>C		intron_variant	Intron 64 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.5137-11T>C		intron_variant	Intron 64 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

723

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00144

AC:

351

AN:

244058

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000456

Gnomad OTH exome

AF:

0.000834

GnomAD4 exome

AF:

0.000502

AC:

727

AN:

1448412

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

301

AN XY:

721218

show subpopulations

African (AFR)

AF:

0.0179

AC:

596

AN:

33232

American (AMR)

AF:

0.000989

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25990

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

85624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52164

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

1101636

Other (OTH)

AF:

0.000950

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00474

AC:

722

AN:

152180

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0162

AC:

674

AN:

41524

American (AMR)

AF:

0.00235

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68006

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00565

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 26, 2013

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.

Aug 10, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 15, 2022

Genome-Nilou Lab

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

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal

Benign:1

Jul 02, 2021

Fulgent Genetics, Fulgent Genetics

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

-0.88

CADD

Benign

1.1

(source)

DANN

Benign

0.48

PhyloP100

-0.36

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over