X-108603054-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_033380.3(COL4A5):​c.2237G>T​(p.Gly746Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

COL4A5
NM_033380.3 missense

Scores

13
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.17
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.2237G>T p.Gly746Val missense_variant 28/53 ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.2237G>T p.Gly746Val missense_variant 28/531 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338.1 linkuse as main transcriptc.1061G>T p.Gly354Val missense_variant 12/201 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkuse as main transcriptc.2237G>T p.Gly746Val missense_variant 28/512 ENSP00000354505.2 P29400-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1041756
Hom.:
0
Cov.:
24
AF XY:
0.00
AC XY:
0
AN XY:
319348
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:
0.00
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
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.81
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.94
.;D;D
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
D;D;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
4.8
H;H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
D
PROVEAN
Pathogenic
-8.0
D;D;.
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0020
D;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
1.0
.;D;D
Vest4
0.99
MutPred
0.97
Loss of glycosylation at P745 (P = 0.115);Loss of glycosylation at P745 (P = 0.115);.;
MVP
0.99
MPC
0.37
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
1.0

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: rs867625069; hg19: chrX-107846284; API