rs104886399

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4BS2

The NM_033380.3(COL4A5):​c.3923A>G​(p.Gln1308Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,209,134 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 24)
Exomes 𝑓: 0.000022 ( 0 hom. 10 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

3
5
9

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.19
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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_033380.3
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.3822859).
BS2
High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A5NM_033380.3 linkc.3923A>G p.Gln1308Arg missense_variant Exon 44 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.3923A>G p.Gln1308Arg missense_variant Exon 44 of 53 1 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000361603.7 linkc.3905A>G p.Gln1302Arg missense_variant Exon 42 of 51 2 ENSP00000354505.2 P29400-1
COL4A5ENST00000489230.1 linkn.326A>G non_coding_transcript_exon_variant Exon 3 of 8 5
COL4A5ENST00000510690.2 linkn.417A>G non_coding_transcript_exon_variant Exon 2 of 11 4

Frequencies

GnomAD3 genomes
AF:
0.0000535
AC:
6
AN:
112080
Hom.:
0
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000948
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000562
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000564
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000383
AC:
7
AN:
182905
AF XY:
0.0000593
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000732
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000613
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
24
AN:
1097054
Hom.:
0
Cov.:
30
AF XY:
0.0000276
AC XY:
10
AN XY:
362700
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
26362
Gnomad4 AMR exome
AF:
0.0000854
AC:
3
AN:
35136
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
19346
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
30155
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
54105
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
40478
Gnomad4 NFE exome
AF:
0.0000202
AC:
17
AN:
841340
Gnomad4 Remaining exome
AF:
0.0000652
AC:
3
AN:
46029
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000535
AC:
6
AN:
112080
Hom.:
0
Cov.:
24
AF XY:
0.0000876
AC XY:
3
AN XY:
34238
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.0000948
AC:
0.0000948497
AN:
0.0000948497
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.000562
AC:
0.00056164
AN:
0.00056164
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000564
AC:
0.0000564323
AN:
0.0000564323
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000341
Hom.:
0
Bravo
AF:
0.000106
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000238

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jan 17, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

X-linked Alport syndrome Benign:1
Feb 27, 2020
Natera, Inc.
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.38
CADD
Benign
19
DANN
Benign
0.86
DEOGEN2
Uncertain
0.46
.;T
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.79
T;T
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
0.33
.;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.78
N;N
REVEL
Uncertain
0.48
Sift
Benign
0.48
T;T
Sift4G
Benign
0.55
T;T
Polyphen
0.64
.;P
Vest4
0.31
MutPred
0.37
.;Gain of methylation at Q1302 (P = 0.0168);
MVP
1.0
MPC
0.32
ClinPred
0.15
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.52
gMVP
0.29
Mutation Taster
=98/2
polymorphism

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: rs104886399; hg19: chrX-107920844; API