19-9967905-G-A

Variant summary

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

The ENST00000264828.4(COL5A3):​c.4403C>T​(p.Pro1468Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

COL5A3
ENST00000264828.4 missense, splice_region

Scores

5
14
Splicing: ADA: 0.0005463
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53
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=0.19276375).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL5A3NM_015719.4 linkuse as main transcriptc.4403C>T p.Pro1468Leu missense_variant, splice_region_variant 61/67 ENST00000264828.4 NP_056534.2
COL5A3XM_011528042.3 linkuse as main transcriptc.4400C>T p.Pro1467Leu missense_variant, splice_region_variant 61/67 XP_011526344.1
COL5A3XM_017026849.2 linkuse as main transcriptc.2066C>T p.Pro689Leu missense_variant, splice_region_variant 34/40 XP_016882338.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL5A3ENST00000264828.4 linkuse as main transcriptc.4403C>T p.Pro1468Leu missense_variant, splice_region_variant 61/671 NM_015719.4 ENSP00000264828 P1
COL5A3ENST00000461214.1 linkuse as main transcriptn.496C>T non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
9
AN:
249796
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135124
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000532
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000705
AC:
103
AN:
1460868
Hom.:
0
Cov.:
31
AF XY:
0.0000784
AC XY:
57
AN XY:
726686
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000801
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000966
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 28, 2022The c.4403C>T (p.P1468L) alteration is located in exon 61 (coding exon 61) of the COL5A3 gene. This alteration results from a C to T substitution at nucleotide position 4403, causing the proline (P) at amino acid position 1468 to be replaced by a leucine (L). 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
0.072
BayesDel_addAF
Benign
-0.043
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
21
DANN
Benign
0.94
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.19
T
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.1
D
REVEL
Uncertain
0.39
Sift
Uncertain
0.022
D
Sift4G
Benign
0.18
T
Polyphen
0.0020
B
Vest4
0.11
MutPred
0.32
Gain of MoRF binding (P = 0.0449);
MVP
0.81
MPC
0.11
ClinPred
0.067
T
GERP RS
2.4
Varity_R
0.13
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00055
dbscSNV1_RF
Benign
0.036
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs571945809; hg19: chr19-10078581; API