19-9966572-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015719.4(COL5A3):​c.4633C>T​(p.His1545Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

COL5A3
NM_015719.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45
Variant links:
Genes affected
COL5A3 (HGNC:14864): (collagen type V alpha 3 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. Mutations in this gene are thought to be responsible for the symptoms of a subset of patients with Ehlers-Danlos syndrome type III. Messages of several sizes can be detected in northern blots but sequence information cannot confirm the identity of the shorter messages. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24031037).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL5A3NM_015719.4 linkc.4633C>T p.His1545Tyr missense_variant Exon 63 of 67 ENST00000264828.4 NP_056534.2 P25940
COL5A3XM_011528042.3 linkc.4630C>T p.His1544Tyr missense_variant Exon 63 of 67 XP_011526344.1
COL5A3XM_017026849.2 linkc.2296C>T p.His766Tyr missense_variant Exon 36 of 40 XP_016882338.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL5A3ENST00000264828.4 linkc.4633C>T p.His1545Tyr missense_variant Exon 63 of 67 1 NM_015719.4 ENSP00000264828.3 P25940

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 16, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4633C>T (p.H1545Y) alteration is located in exon 63 (coding exon 63) of the COL5A3 gene. This alteration results from a C to T substitution at nucleotide position 4633, causing the histidine (H) at amino acid position 1545 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.094
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.072
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.46
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.24
T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
1.7
L
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.11
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.090
B
Vest4
0.19
MutPred
0.59
Loss of disorder (P = 0.0306);
MVP
0.77
MPC
1.8
ClinPred
0.39
T
GERP RS
0.75
Varity_R
0.22
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10077248; API