X-108680941-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_033380.3(COL4A5):​c.4072C>G​(p.Leu1358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,356 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1358I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)
Exomes š‘“: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

4
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.838
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_033380.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16583315).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A5NM_033380.3 linkc.4072C>G p.Leu1358Val missense_variant Exon 46 of 53 ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkc.4072C>G p.Leu1358Val missense_variant Exon 46 of 53 1 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000361603.7 linkc.4054C>G p.Leu1352Val missense_variant Exon 44 of 51 2 ENSP00000354505.2 P29400-1
COL4A5ENST00000489230.1 linkn.475C>G non_coding_transcript_exon_variant Exon 5 of 8 5
COL4A5ENST00000510690.2 linkn.566C>G non_coding_transcript_exon_variant Exon 4 of 11 4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
9.15e-7
AC:
1
AN:
1093356
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
358928
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
14
DANN
Benign
0.94
DEOGEN2
Benign
0.11
.;T
FATHMM_MKL
Benign
0.13
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
0.94
.;L
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.22
N;N
REVEL
Uncertain
0.40
Sift
Benign
0.61
T;T
Sift4G
Benign
0.68
T;T
Polyphen
0.023
.;B
Vest4
0.12
MutPred
0.34
.;Loss of glycosylation at P1356 (P = 0.2061);
MVP
0.92
MPC
0.32
ClinPred
0.17
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.15
gMVP
0.078

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-107924171; API