9-134642215-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000093.5(COL5A1):c.28C>T(p.Arg10Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,304,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R10R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0840

Publications

0 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2461114).

BP6

Variant 9-134642215-C-T is Benign according to our data. Variant chr9-134642215-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459666.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 66		NP_001265003.1
COL5A1	XM_017014266.3 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.28C>T	p.Arg10Cys	missense_variant	Exon 1 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.0000465

AC:

AN:

150692

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000104

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000354

AC:

AN:

56554

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000465

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1154118

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

560848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23778

American (AMR)

AF:

0.0000547

AC:

AN:

18270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18382

East Asian (EAS)

AF:

0.00

AC:

AN:

24920

South Asian (SAS)

AF:

0.00

AC:

AN:

38856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

956310

Other (OTH)

AF:

0.00

AC:

AN:

45808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000465

AC:

AN:

150692

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

73558

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41228

American (AMR)

AF:

0.00

AC:

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

67552

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 11, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22696272) -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL5A1-related disorder

Uncertain:1

Apr 01, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL5A1 c.28C>T variant is predicted to result in the amino acid substitution p.Arg10Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-137534061-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.084

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.89

N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.0010

B;.

Vest4

0.13

MutPred

0.41

Loss of MoRF binding (P = 0.0029);Loss of MoRF binding (P = 0.0029);

MVP

0.54

MPC

0.50

ClinPred

0.17

GERP RS

1.4

PromoterAI

0.012

Neutral

(source)

Varity_R

0.11

gMVP

0.37

Mutation Taster

=81/19

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over