rs104886129

Variant names:

• chrX-108597461-G-C
• rs104886129
• NM_033380.3:c.1672G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.1672G>C​(p.Gly558Arg) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_033380.3 (COL4A5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-108597461-G-C is Pathogenic according to our data. Variant chrX-108597461-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3766541.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108597461-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1672G>C	p.Gly558Arg	missense_variant	Exon 24 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1672G>C	p.Gly558Arg	missense_variant	Exon 24 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.496G>C	p.Gly166Arg	missense_variant	Exon 8 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1672G>C	p.Gly558Arg	missense_variant	Exon 24 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

Apr 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A5 c.1672G>C; p.Gly558Arg variant (rs104886129) is reported in the literature in an individual affected with Alport syndrome (Barker 2001). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.975). Variants that create or remove a glycine in Gly-X-Y domains are often deleterious due to glycine repeats (Persikov 2004, Weerakkody 2016). Additionally, other amino acid substitutions at this codon (Gly558Asp, Gly558Ser, Gly558Val) have been reported in individuals with Alport syndrome and are considered disease causing (Bekheirnia 2010, Di 2022). Based on available information, this variant is considered to be likely pathogenic. References: Barker DF et al. Efficient detection of Alport syndrome COL4A5 mutations with multiplex genomic PCR-SSCP. Am J Med Genet. 2001 Jan 15;98(2):148-60. PMID: 11223851. Bekheirnia MR et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol. 2010 May;21(5):876-83. PMID: 20378821. Di H et al. Dissecting the genotype-phenotype correlation of COL4A5 gene mutation and its response to renin-angiotensin-aldosterone system blockers in Chinese male patients with Alport syndrome. Nephrol Dial Transplant. 2022 Nov 23;37(12):2487-2495. PMID: 35020912. Persikov AV et al. Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum Mutat. 2004 Oct;24(4):330-7. PMID: 15365990. Weerakkody RA et al. Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome. Genet Med. 2016 Nov;18(11):1119-1127. PMID: 27011056. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.8	D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.95
MutPred		0.85		Loss of methylation at K557 (P = 0.07);Loss of methylation at K557 (P = 0.07);.;
MVP		0.99
MPC		0.36
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs104886129; hg19: chrX-107840691;