9-134835184-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_000093.5(COL5A1):c.5350G>T(p.Ala1784Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A1784T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.92

Publications

8 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:

LOC101448202 (HGNC:):

LOC101448202 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

BP6

Variant 9-134835184-G-T is Benign according to our data. Variant chr9-134835184-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 853518.

BS2

High AC in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL5A1	NM_000093.5	MANE Select	c.5350G>T	p.Ala1784Ser	missense	Exon 65 of 66	NP_000084.3
COL5A1	NM_001278074.1		c.5350G>T	p.Ala1784Ser	missense	Exon 65 of 66	NP_001265003.1	P20908-2
LOC101448202	NR_103451.2		n.71-14975C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.5350G>T	p.Ala1784Ser	missense	Exon 65 of 66	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4	TSL:2	c.5350G>T	p.Ala1784Ser	missense	Exon 65 of 66	ENSP00000360885.4	P20908-2
COL5A1	ENST00000950240.1		c.5341G>T	p.Ala1781Ser	missense	Exon 65 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461268

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111962

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

3.3

PhyloP100

7.9

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.60

Sift

Uncertain

0.025

Sift4G

Uncertain

0.037

Polyphen

1.0

Vest4

0.63

MutPred

0.55

Loss of stability (P = 0.0546)

MVP

0.79

MPC

0.27

ClinPred

0.69

GERP RS

5.0

Varity_R

0.69

gMVP

0.53

Mutation Taster

=63/37

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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