X-108440126-A-G

Variant names:

• chrX-108440126-A-G
• rs104886050
• NM_033380.3:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Supporting 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 11 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 324 CDS bases. Genomic position: 108568761. Lost 0.064 part of the original CDS.
• 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 rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.1A>G	p.Met1?	start_lost	Exon 1 of 51		NP_000486.1
COL4A5	XM_047441811.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 42		XP_047297767.1
COL4A5	XM_047441810.1	c.-376A>G		5_prime_UTR_variant	Exon 1 of 54		XP_047297766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7

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

Aug 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. 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 is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the COL4A5 mRNA. The next in-frame methionine is located at codon 109. -

X-linked Alport syndrome Pathogenic:1

Apr 30, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.12	.;T
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
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;