rs534522842

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000092.5(COL4A4):​c.1045C>T​(p.Arg349Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,290 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

COL4A4
NM_000092.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 3.53
Variant links:
Genes affected
COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-227099674-G-A is Pathogenic according to our data. Variant chr2-227099674-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227099674-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A4NM_000092.5 linkuse as main transcriptc.1045C>T p.Arg349Ter stop_gained 18/48 ENST00000396625.5 NP_000083.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkuse as main transcriptc.1045C>T p.Arg349Ter stop_gained 18/485 NM_000092.5 ENSP00000379866 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249414
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135318
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152290
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsDec 28, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2024This sequence change creates a premature translational stop signal (p.Arg349*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs534522842, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 33532864). ClinVar contains an entry for this variant (Variation ID: 447178). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 01, 2021- -
Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterresearchMolecular Biology Laboratory, Fundació PuigvertFeb 01, 2020- -
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingSydney Genome Diagnostics, Children's Hospital WestmeadJan 09, 2018This individual is heterozygous for the c.1045C>T p.(Arg349*) variant in the COL4A4 gene. This variant creates a premature stop codon p.(Arg349*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.0004% (1 out of 246, 064 alleles). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, other truncating variants downstream of this amino acid have been described in ClinVar. This variant is considered to be a likely pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
41
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.88
D
MutationTaster
Benign
1.0
A;A
Vest4
0.84
GERP RS
6.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.34
Position offset: 15

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: rs534522842; hg19: chr2-227964390; COSMIC: COSV61629550; COSMIC: COSV61629550; API