rs754948598

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000093.5(COL5A1):​c.1402G>A​(p.Glu468Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,930 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E468Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

1
14
3

Clinical Significance

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

Conservation

PhyloP100: 6.24

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6
Variant 9-134738486-G-A is Benign according to our data. Variant chr9-134738486-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409118.
BS2
High AC in GnomAdExome4 at 32 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

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
COL5A1
NM_000093.5
MANE Select
c.1402G>Ap.Glu468Lys
missense
Exon 10 of 66NP_000084.3
COL5A1
NM_001278074.1
c.1402G>Ap.Glu468Lys
missense
Exon 10 of 66NP_001265003.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
COL5A1
ENST00000371817.8
TSL:1 MANE Select
c.1402G>Ap.Glu468Lys
missense
Exon 10 of 66ENSP00000360882.3
COL5A1
ENST00000371820.4
TSL:2
c.1402G>Ap.Glu468Lys
missense
Exon 10 of 66ENSP00000360885.4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000279
AC:
7
AN:
251284
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461714
Hom.:
1
Cov.:
32
AF XY:
0.0000234
AC XY:
17
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53252
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000198
AC:
22
AN:
1112010
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41460
American (AMR)
AF:
0.0000654
AC:
1
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000412
AC:
5

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
1
Ehlers-Danlos syndrome, classic type, 1 (1)
-
1
-
Familial thoracic aortic aneurysm and aortic dissection (1)
-
1
-
not provided (1)
-
1
-
not specified (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.23
D
MetaRNN
Uncertain
0.65
D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Benign
-0.20
N
PhyloP100
6.2
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-2.8
D
REVEL
Uncertain
0.60
Sift
Benign
0.035
D
Sift4G
Benign
0.17
T
Polyphen
1.0
D
Vest4
0.73
MutPred
0.44
Gain of methylation at E468 (P = 0.0014)
MVP
0.79
MPC
0.67
ClinPred
0.59
D
GERP RS
4.7
Varity_R
0.19
gMVP
0.91
Mutation Taster
=79/21
polymorphism

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

Other links and lift over

dbSNP: rs754948598; hg19: chr9-137630332; API