X-108582920-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_033380.3(COL4A5):​c.973G>C​(p.Gly325Arg) 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Consequence

COL4A5
NM_033380.3 missense

Scores

14
2
1

Clinical Significance

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

Conservation

PhyloP100: 8.10
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 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant X-108582920-G-C is Pathogenic according to our data. Variant chrX-108582920-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 807568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A5NM_033380.3 linkuse as main transcriptc.973G>C p.Gly325Arg missense_variant 17/53 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.973G>C p.Gly325Arg missense_variant 17/531 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338 linkuse as main transcriptc.-204G>C 5_prime_UTR_variant 1/201 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkuse as main transcriptc.973G>C p.Gly325Arg missense_variant 17/512 ENSP00000354505.2 P29400-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
22

ClinVar

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

Submissions by phenotype

X-linked Alport syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional glycine change within the essential G-X-Y repeat (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant, and an alternative nucleotide change resulting in the same protein outcome (c.973G>A) have been reported as pathogenic, and observed in both hemizygous and heterozygous individuals with Alport syndrome (ClinVar, PMID: 11223851, PMID: 15780079, PMID: 30968591, PMID: 36553470). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenJun 07, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.82
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
.;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.4
H;H
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-7.2
D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.99
MutPred
0.95
Loss of methylation at R326 (P = 0.049);Loss of methylation at R326 (P = 0.049);
MVP
1.0
MPC
0.36
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: rs104886088; hg19: chrX-107826150; API