chrX-108440126-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_033380.3(COL4A5):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 20)

Consequence

COL4A5
NM_033380.3 start_lost

Scores

5
5
4

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.78
Variant links:
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 20 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_033380.3 (COL4A5) was described as [Pathogenic] in ClinVar as 2770173
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-108440126-A-G is Pathogenic according to our data. Variant chrX-108440126-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 24214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108440126-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/53 ENST00000328300.11
COL4A5NM_000495.5 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/51
COL4A5XM_047441811.1 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/42
COL4A5XM_047441810.1 linkuse as main transcriptc.-376A>G 5_prime_UTR_variant 1/54

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/531 NM_033380.3 P29400-2

Frequencies

GnomAD3 genomes
Cov.:
20
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
20

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2020This sequence change affects the initiator methionine of the COL4A5 mRNA. The next in-frame methionine is located at codon 109. This variant is not present in population databases (ExAC no frequency). Disruption of this initiator codon has been observed in individual(s) with Alport syndrome (PMID: 24033287, Invitae). ClinVar contains an entry for this variant (Variation ID: 24214). This variant disrupts the p.Gly105 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
X-linked Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityApr 30, 2020This variant is predicted to abolish the native initation codon of COL4A5 and has been previously reported in a patient presenting with presumed X-linked dominant Alport syndrome (end stage-renal disease, family history of similar presentations, no information about hearing). Additionally, this COL4A5 variant is absent from a large population dataset. We consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
.;T
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.53
D
MutationTaster
Benign
1.0
A;A
PROVEAN
Benign
-0.76
N;N
REVEL
Uncertain
0.61
Sift
Uncertain
0.018
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.32
.;B
Vest4
0.88
MutPred
0.92
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
1.0
ClinPred
0.93
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.47
gMVP
0.89

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

LitVar

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

Other links and lift over

dbSNP: rs104886050; hg19: chrX-107683356; API