dbSNP rs863223460: COL5A1:p.Thr1551Ser (chr9-134823423-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000093.5(COL5A1):c.4652C>G(p.Thr1551Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1551P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.03

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28485936).

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.4652C>G	p.Thr1551Ser	missense	Exon 61 of 66	NP_000084.3
COL5A1	NM_001278074.1		c.4652C>G	p.Thr1551Ser	missense	Exon 61 of 66	NP_001265003.1	P20908-2
LOC101448202	NR_103451.2		n.71-3214G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4652C>G	p.Thr1551Ser	missense	Exon 61 of 66	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4	TSL:2	c.4652C>G	p.Thr1551Ser	missense	Exon 61 of 66	ENSP00000360885.4	P20908-2
COL5A1	ENST00000950240.1		c.4643C>G	p.Thr1548Ser	missense	Exon 61 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.00078

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.16

Eigen_PC

Benign

0.024

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

M_CAP

Benign

0.060

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.32

PhyloP100

6.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.77

REVEL

Benign

0.28

Sift

Benign

0.25

Sift4G

Benign

0.43

Polyphen

0.0030

Vest4

0.29

MutPred

0.31

Gain of glycosylation at T1551 (P = 0.1589)

MVP

0.44

MPC

0.27

ClinPred

0.79

GERP RS

4.2

Varity_R

0.087

gMVP

0.22

Mutation Taster

=64/36

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over