rs104886199

Positions:

• chrX-108620382-G-A
• chrX-108620382-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.2633G>A​(p.Gly878Glu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G878R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.95

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 18 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 31) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant X-108620382-G-A is Pathogenic according to our data. Variant chrX-108620382-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 968858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108620382-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2633G>A	p.Gly878Glu	missense_variant	31/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2633G>A	p.Gly878Glu	missense_variant	31/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1457G>A	p.Gly486Glu	missense_variant	15/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2633G>A	p.Gly878Glu	missense_variant	31/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2019

This sequence change replaces glycine with glutamic acid at codon 878 of the COL4A5 protein (p.Gly878Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Alport syndrome (PMID: 28542346, Invitae). For these reasons, this variant has been classified as Pathogenic. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). -

Alport syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 10, 2017

This individual is hemizygous for the variant, c.2633G>A p.(Gly878Glu), in the COL4A5 gene. The c.2633G>A variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP). This variant results in substitution of one of the invariant glycine residues within the triple helical domain of the alpha 5 chain of type IV collagen. This variant has been previously reported in the hemizygote state in a male patient with X-linked Alport syndrome (Liu et al 2017 PLoS One 12(5):e0177685. PMID:28542346). This variant is considered to likely pathogenic according to the ACMG guidelines. -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.4	D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		1.0
MutPred		0.65		Loss of glycosylation at S879 (P = 0.0708);Loss of glycosylation at S879 (P = 0.0708);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		6.2
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

Other links and lift over

dbSNP: rs104886199; hg19: chrX-107863612; COSMIC: COSV60356471; COSMIC: COSV60356471;