rs104886079

Positions:

• chrX-108580731-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.884G>A​(p.Gly295Asp) 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.12

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-108580731-G-A is Pathogenic according to our data. Variant chrX-108580731-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108580731-G-A is described in Lovd as [Pathogenic]. Variant chrX-108580731-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.884G>A	p.Gly295Asp	missense_variant	15/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.884G>A	p.Gly295Asp	missense_variant	15/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.884G>A	p.Gly295Asp	missense_variant	15/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 13, 2024	PP3, PM1_strong, PM2, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 17, 2017	- -

X-linked Alport syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 10, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 20, 2017	- -

Alport syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Sep 15, 2017

This individual is hemizygous for a variant, c.884G>A p.(Gly295Asp), in the COL4A5 gene. The c.884G>A variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP).It has been previously described in an affected male individual with Alport Syndrome (Barker et al Am J Med Genet 2001 15;98(2):148-160). This variant results in the substitution of one of the invariant glycine residues within the triple helical domain. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggested that this variant is pathogenic. This variant is considered to be a likely pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
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	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.6	H;H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.5	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		0.98		Gain of ubiquitination at K299 (P = 0.0638);Gain of ubiquitination at K299 (P = 0.0638);
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104886079; hg19: chrX-107823961;