rs104886101

Variant names:

• chrX-108591118-G-A
• rs104886101
• NM_033380.3:c.1226G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108591118-G-A
• chrX-108591118-G-C
• chrX-108591118-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.1226G>A​(p.Gly409Asp) 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. G409V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.07
• Publications: 8 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 19 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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-108591118-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1676179.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, 0.993
• PP5: Variant X-108591118-G-A is Pathogenic according to our data. Variant chrX-108591118-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 24386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1226G>A	p.Gly409Asp	missense_variant	Exon 20 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1226G>A	p.Gly409Asp	missense_variant	Exon 20 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.50G>A	p.Gly17Asp	missense_variant	Exon 4 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1226G>A	p.Gly409Asp	missense_variant	Exon 20 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Alport syndrome Pathogenic:3

Dec 01, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2023

Precision Medicine Center, Zhengzhou University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1_strong,PM2_p,PM5_strong,PP3_strong -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1226G>A p.Gly409Asp variant in COL4A5 gene has been reported in multiple individuals affected with Alport syndrome Yeo J et al. 2020; Gillion V et al. 2018; Mansilla MA et al. 2021. It has also been observed to segregate with disease in related individuals. The p.Gly409Asp variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submiters. The amino acid change p.Gly409Asp in COL4A5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 409 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Aug 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1226G>A (p.G409D) alteration is located in exon 20 (coding exon 20) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 1226, causing the glycine (G) at amino acid position 409 to be replaced by an aspartic acid (D). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with Alport syndrome (Renieri, 1996; Mallett, 2017; Mansilla, 2021; Lujinschi, 2024) and this variant segregated with disease in one family (Zholdybayeva, 2014). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Alport syndrome Pathogenic:1

Sep 06, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This patient is heterozygous for a known pathogenic variant, c.1226G>A (p.Gly409Asp), in exon 20 of the COL4A5 gene. This variant results in substitution of one of the invariant glycine residues in the triple helical domain of type IV collagen and is considered to be pathogenic. This variant has been reported as pathogenic in the COL4A5 Alport database (http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php). -

COL4A5-related disorder Pathogenic:1

Jan 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A5 c.1226G>A variant is predicted to result in the amino acid substitution p.Gly409Asp. This variant was reported in an individual with Alport syndrome (Renieri et al 1996. PubMed ID: 8651296). This variant was also reported to segregate in a large family in individuals with features of COL4A5-related disorders (Zholdybayeva EV et al 2014. PubMed ID: 25572247). The p.Gly409 residue resides in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org). The majority of pathogenic variants in COL4A5 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 409 of the COL4A5 protein (p.Gly409Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alport syndrome (PMID: 8651296, 25572247). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24386). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A5 protein function with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.
PhyloP100		9.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D;D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0040	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.99
MutPred		0.99		Gain of solvent accessibility (P = 0.0149);Gain of solvent accessibility (P = 0.0149);.;
MVP		0.99
MPC		0.39
ClinPred		1.0	D
GERP RS		5.3
Varity_R		1.0
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104886101; hg19: chrX-107834348;