rs104886209

Variant names:

• chrX-108625768-G-A
• rs104886209
• NM_033380.3:c.3080G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108625768-G-A
• chrX-108625768-G-T

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.3080G>A​(p.Gly1027Glu) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G1027R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.13

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

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 2 benign, 2 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-108625767-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067288.Status of the report is criteria_provided_single_submitter, 1 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). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-108625768-G-A is Pathogenic according to our data. Variant chrX-108625768-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066731.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.3080G>A	p.Gly1027Glu	missense_variant	Exon 35 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3080G>A	p.Gly1027Glu	missense_variant	Exon 35 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1904G>A	p.Gly635Glu	missense_variant	Exon 19 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.3080G>A	p.Gly1027Glu	missense_variant	Exon 35 of 51	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.311G>A	p.Gly104Glu	missense_variant	Exon 3 of 5	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with glutamic acid at codon 1027 of the COL4A5 protein (p.Gly1027Glu). 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 disrupts the p.Gly1027 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 15780079), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL4A5. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A5 protein function. This variant has been observed in individual(s) with clinical features of Alport syndrome (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.2	D;D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.96		Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);.;
MVP		0.99
MPC		0.39
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs104886209; hg19: chrX-107868998; COSMIC: COSV60358130;