rs41310213

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000093.5(COL5A1):c.2431-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,611,960 control chromosomes in the GnomAD database, including 15,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2341 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12679 hom. )

Consequence

COL5A1
NM_000093.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.832

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: 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:

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=-0.98).

BP6

Variant 9-134782642-G-A is Benign according to our data. Variant chr9-134782642-G-A is described in ClinVar as Benign. ClinVar VariationId is 255062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.2431-25G>A	intron_variant	Intron 28 of 65	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.2431-25G>A	intron_variant	Intron 28 of 65		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.2431-25G>A	intron_variant	Intron 28 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.2431-25G>A		intron_variant	Intron 28 of 65	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820.4 link	c.2431-25G>A		intron_variant	Intron 28 of 65	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.162

AC:

24632

AN:

152046

Hom.:

2338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.257

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0999

Gnomad ASJ

AF:

0.131

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.0729

Gnomad FIN

AF:

0.160

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.129

Gnomad OTH

AF:

0.167

GnomAD2 exomes

AF:

0.130

AC:

32661

AN:

251096

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.0747

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.128

AC:

186228

AN:

1459796

Hom.:

12679

Cov.:

AF XY:

0.126

AC XY:

91468

AN XY:

726368

show subpopulations

African (AFR)

AF:

0.264

AC:

8813

AN:

33426

American (AMR)

AF:

0.0787

AC:

3520

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

3341

AN:

26130

East Asian (EAS)

AF:

0.138

AC:

5487

AN:

39684

South Asian (SAS)

AF:

0.0774

AC:

6670

AN:

86220

European-Finnish (FIN)

AF:

0.156

AC:

8306

AN:

53236

Middle Eastern (MID)

AF:

0.115

AC:

663

AN:

5766

European-Non Finnish (NFE)

AF:

0.127

AC:

141117

AN:

1110278

Other (OTH)

AF:

0.138

AC:

8311

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7948

15896

23844

31792

39740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5168

10336

15504

20672

25840

<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:

0.162

AC:

24655

AN:

152164

Hom.:

2341

Cov.:

AF XY:

0.159

AC XY:

11803

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.257

AC:

10659

AN:

41502

American (AMR)

AF:

0.0998

AC:

1527

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

453

AN:

3470

East Asian (EAS)

AF:

0.155

AC:

796

AN:

5148

South Asian (SAS)

AF:

0.0726

AC:

350

AN:

4824

European-Finnish (FIN)

AF:

0.160

AC:

1696

AN:

10608

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.129

AC:

8781

AN:

68002

Other (OTH)

AF:

0.165

AC:

348

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1039

2079

3118

4158

5197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.143

Hom.:

324

Bravo

AF:

0.164

Asia WGS

AF:

0.135

AC:

472

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

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

- -

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: The COL5A1 c.2431-25G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing while ESE finder predicts the loss of a SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. This variant was found in 16316/120916 control chromosomes (1295 homozygotes) at a frequency of 0.1349367, which is approximately 107949 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory and one reputable database classified this variant as benign. Taken together, this variant is classified as benign. -

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

-0.98

CADD

Benign

4.3

(source)

DANN

Benign

0.49

PhyloP100

0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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