rs104886050

Positions:

• chrX-108440126-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.1A>G​(p.Met1?) variant causes a start lost change. 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 (★★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: COL4A5 NM_033380.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.78

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_033380.3 (COL4A5) was described as [Pathogenic] in ClinVar as 2770173
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108440126-A-G is Pathogenic according to our data. Variant chrX-108440126-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 24214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108440126-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1A>G	p.Met1?	start_lost	1/53	ENST00000328300.11
COL4A5	NM_000495.5	c.1A>G	p.Met1?	start_lost	1/51
COL4A5	XM_047441811.1	c.1A>G	p.Met1?	start_lost	1/42
COL4A5	XM_047441810.1	c.-376A>G		5_prime_UTR_variant	1/54

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1A>G	p.Met1?	start_lost	1/53	1	NM_033380.3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2020

This sequence change affects the initiator methionine of the COL4A5 mRNA. The next in-frame methionine is located at codon 109. This variant is not present in population databases (ExAC no frequency). Disruption of this initiator codon has been observed in individual(s) with Alport syndrome (PMID: 24033287, Invitae). ClinVar contains an entry for this variant (Variation ID: 24214). This variant disrupts the p.Gly105 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Apr 30, 2020

This variant is predicted to abolish the native initation codon of COL4A5 and has been previously reported in a patient presenting with presumed X-linked dominant Alport syndrome (end stage-renal disease, family history of similar presentations, no information about hearing). Additionally, this COL4A5 variant is absent from a large population dataset. We consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	19
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	A;A
PROVEAN	Benign	-0.76	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.018	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.32	.;B
Vest4		0.88
MutPred		0.92		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		1.0
ClinPred		0.93	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.89

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: rs104886050; hg19: chrX-107683356;