rs104886130

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_033380.3(COL4A5):​c.1736G>A​(p.Gly579Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G579R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

COL4A5
NM_033380.3 missense

Scores

14
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.95
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 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant X-108597525-G-A is Pathogenic according to our data. Variant chrX-108597525-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2439396.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108597525-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.1736G>A p.Gly579Glu missense_variant 24/53 ENST00000328300.11 NP_203699.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkuse as main transcriptc.1736G>A p.Gly579Glu missense_variant 24/531 NM_033380.3 ENSP00000331902 P29400-2
COL4A5ENST00000483338.1 linkuse as main transcriptc.560G>A p.Gly187Glu missense_variant 8/201 ENSP00000495685
COL4A5ENST00000361603.7 linkuse as main transcriptc.1736G>A p.Gly579Glu missense_variant 24/512 ENSP00000354505 P1P29400-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 22, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.82
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.73
.;D;T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.8
H;H;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-7.7
D;D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
.;D;D
Vest4
1.0
MutPred
0.97
Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);.;
MVP
1.0
MPC
0.39
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.97
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: rs104886130; hg19: chrX-107840755; API