rs104886094
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_033380.3(COL4A5):c.1117C>T(p.Arg373Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R373R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 21)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
COL4A5
NM_033380.3 stop_gained
NM_033380.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 1.97
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant X-108586699-C-T is Pathogenic according to our data. Variant chrX-108586699-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 24367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108586699-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1117C>T | p.Arg373Ter | stop_gained | 19/53 | ENST00000328300.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1117C>T | p.Arg373Ter | stop_gained | 19/53 | 1 | NM_033380.3 | ||
COL4A5 | ENST00000483338.1 | c.-60C>T | 5_prime_UTR_variant | 3/20 | 1 | ||||
COL4A5 | ENST00000361603.7 | c.1117C>T | p.Arg373Ter | stop_gained | 19/51 | 2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD3 genomes
?
Cov.:
21
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1096548Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 362218
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1096548
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Cov.:
30
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0
AN XY:
362218
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 21
GnomAD4 genome
?
Cov.:
21
ExAC
?
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1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Adequate data is not available in large population cohorts to assess the frequency of this variant in publicly available databases; however, this variant has not been detected in presumably healthy individuals tested at GeneDx; This variant is associated with the following publications: (PMID: 25525159, 8738805, 8940267, 30577881, 33330536, 10862091, 8651296, 19965530) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg373*) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a clinical diagnosis or clinical features of Alport syndrome (PMID: 8651296, 30577881). This variant is also known as 1319C>T, R373X. ClinVar contains an entry for this variant (Variation ID: 24367). For these reasons, this variant has been classified as Pathogenic. - |
X-linked Alport syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 23, 2021 | - - |
COL4A5-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 20, 2023 | The COL4A5 c.1117C>T variant is predicted to result in premature protein termination (p.Arg373*). This variant was reported in individuals with Alport syndrome (Renieri et al 1996. PubMed ID: 8651296; Zhang X et al 2018. PubMed ID: 30577881). This variant was also reported in a female patient with features of COL45A-related disorders (Table 2, patient #7 Mastrangelo A et al 2020. PubMed ID: 33330536). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in COL4A5 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at