9-134818991-C-T

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.4393-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,613,360 control chromosomes in the GnomAD database, including 978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 55 hom., cov: 32)

Exomes 𝑓: 0.032 ( 923 hom. )

Consequence

COL5A1
NM_000093.5 intron

Scores

Splicing: ADA: 0.00003457

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0780

Publications

7 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
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:

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=-0.56).

BP6

Variant 9-134818991-C-T is Benign according to our data. Variant chr9-134818991-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3790/152302) while in subpopulation NFE AF = 0.0331 (2248/68002). AF 95% confidence interval is 0.0319. There are 55 homozygotes in GnomAd4. There are 1887 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3790 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.4393-9C>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.4393-9C>T		intron	N/A	NP_001265003.1	P20908-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4393-9C>T	intron	N/A	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4	TSL:2	c.4393-9C>T	intron	N/A	ENSP00000360885.4	P20908-2
COL5A1	ENST00000950240.1		c.4384-9C>T	intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3793

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00685

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.0769

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0445

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0265

AC:

6661

AN:

251182

AF XY:

0.0262

show subpopulations

Gnomad AFR exome

AF:

0.00653

Gnomad AMR exome

AF:

0.0218

Gnomad ASJ exome

AF:

0.0738

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0394

Gnomad NFE exome

AF:

0.0343

Gnomad OTH exome

AF:

0.0310

GnomAD4 exome

AF:

0.0324

AC:

47345

AN:

1461058

Hom.:

923

Cov.:

AF XY:

0.0316

AC XY:

22963

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.00466

AC:

156

AN:

33480

American (AMR)

AF:

0.0224

AC:

1000

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0763

AC:

1995

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00451

AC:

389

AN:

86256

European-Finnish (FIN)

AF:

0.0356

AC:

1879

AN:

52716

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0360

AC:

39994

AN:

1111900

Other (OTH)

AF:

0.0308

AC:

1858

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2426

4852

7278

9704

12130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1516

3032

4548

6064

7580

<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:

0.0249

AC:

3790

AN:

152302

Hom.:

Cov.:

AF XY:

0.0253

AC XY:

1887

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00683

AC:

284

AN:

41576

American (AMR)

AF:

0.0266

AC:

407

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0769

AC:

267

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00580

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0445

AC:

472

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0331

AC:

2248

AN:

68002

Other (OTH)

AF:

0.0341

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

187

374

562

749

936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0272

Hom.:

Bravo

AF:

0.0242

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0351

EpiControl

AF:

0.0340

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Ehlers-Danlos syndrome, classic type, 1 (2)

not provided (2)

Ehlers-Danlos syndrome (1)

Ehlers-Danlos syndrome type 7A (1)

Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

-0.078

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000035

dbscSNV1_RF

Benign

0.16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over