rs104886210

Positions:

• chrX-108625776-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.3088G>A​(p.Gly1030Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,085,171 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.28

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, 0.992
• PP5: Variant X-108625776-G-A is Pathogenic according to our data. Variant chrX-108625776-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108625776-G-A is described in Lovd as [Pathogenic]. Variant chrX-108625776-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.3088G>A	p.Gly1030Ser	missense_variant	35/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3088G>A	p.Gly1030Ser	missense_variant	35/53	1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000483338.1	c.1912G>A	p.Gly638Ser	missense_variant	19/20	1		ENSP00000495685
COL4A5	ENST00000361603.7	c.3088G>A	p.Gly1030Ser	missense_variant	35/51	2		ENSP00000354505	P1
COL4A5	ENST00000505728.1	c.322G>A	p.Gly108Ser	missense_variant	3/5	3		ENSP00000424137

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1085171 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 351417

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2023	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (HGMD; Jais et al., 2000); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15044104, 19919694, 29526710, 32405592, 9848783, 29127259, 15780079, 15347445, 33040356) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	COL4A5: PM1:Strong, PM2, PS4:Moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1030 of the COL4A5 protein (p.Gly1030Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 9848783, 24130771). ClinVar contains an entry for this variant (Variation ID: 24591). 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 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. -

X-linked Alport syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 21, 2022	- -

Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 25, 2021

The COL4A5 c.3088G>A (p.Gly1030Ser) variant is a missense variant that has been reported in a hemizygous state in three male individuals and in a heterozygous state in one female individual with Alport syndrome (Martin et al. 1998; Wang et al. 2004; Liu et al. 2017; Kamura et al. 2020). All the affected individuals presented with hematuria, with two individuals also presenting with sensorineural hearing loss. The p.Gly1030Ser variant segregated in one family in which it was present in the affected father and son (Kamura et al. 2020). This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so is presumed to be rare. Glycine substitutions in missense variants in the collagenous domain are the most common variant type found in X-linked Alport syndrome (Kamura et al. 2020). Circular dichroism spectroscopy studies showed that the p.Gly1030Ser variant affected secondary structure of the protein and results in less beta-sheet and more random coil structure compared to wild type (Wang et al. 2004). In addition, expression of the p.Gly1030Ser variant in HEK293T cells showed a significant reduction of over 50% in extracellular secretion of COL4A5 compared to wild type (Kamura et al. 2020). Based on the collective evidence, the p.Gly1030Ser variant is classified as likely pathogenic for Alport syndrome. -

Nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.9	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.99		Gain of glycosylation at G1030 (P = 0.0225);Gain of glycosylation at G1030 (P = 0.0225);.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
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: rs104886210; hg19: chrX-107869006;