rs104886129

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 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. 12/21 in silico tools predict a damaging 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. G558D) has been classified as Pathogenic.

• 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
• Publications: 2 publications found

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]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 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, 6 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108597462-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 807571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• 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 VariationId is 3766541.Status of the report is criteria_provided_single_submitter, 1 stars.

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;.
PhyloP100		10
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104886129; hg19: chrX-107840691;