rs104886314

Variant names:

• chrX-108584525-TGTAA-T
• rs104886314
• NM_033380.3:c.1032+3_1032+6delAAGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_033380.3(COL4A5):​c.1032+3_1032+6delAAGT variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 6.37
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108584525-TGTAA-T is Pathogenic according to our data. Variant chrX-108584525-TGTAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24356.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1032+3_1032+6delAAGT		splice_region_variant, intron_variant	Intron 18 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1032+1_1032+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 18 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.-145+1_-145+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 2 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1032+1_1032+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 18 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

See cases Pathogenic:1

Nov 25, 2020

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We observed the genetic variant c.1032+3_1032+6del in COL4A5 gene in a male 24-y.o. proband diagnosed with Alport syndrome and dilated cardiomyopathy. To our knowledge, the c.1032+3_1032+6del variant is absent from large population studies, which makes it rare (PM2 criteria). According to in silico splice site prediction tools (PP3), this variant alters canonical splice sites, therefore, leading to the changes in protein length (PM4). The phenotype of our patient and his family history are highly illustrative (PP4). The mode of inheritance is X-linked recessive, with severe clinical symptoms in men and relatively mild symptoms of kidney disorder in women. Additionally, this variant was previously reported as Pathogenic, though no functional studies are available to date (PP5). Because of the combination of listed criteria we classify the c.1032+3_1032+6del variant as likely pathogenic. -

not provided Pathogenic:1

Jul 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as 1234+3delAAGT. This variant has been observed in individuals with X-linked Alport syndrome (PMID: 8940267, 29959198; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 18 of the COL4A5 gene. It does not directly change the encoded amino acid sequence of the COL4A5 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. ClinVar contains an entry for this variant (Variation ID: 24356). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 18, but is expected to preserve the integrity of the reading-frame (PMID: 29959198). -

Inborn genetic diseases Uncertain:1

Apr 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1032+3_1032+6delAAGT intronic variant begins 3 nucleotides after coding exon 18 in the COL4A5 gene. This variant results from a deletion of 4 nucleotides at positions c.1032+3 to c.1032+6. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in individuals with clinical features of COL4A5-related Alport syndrome (Knebelmann, 1996; Horinouchi, 2018; external communication). This nucleotide position is well conserved in available vertebrate species. RT-PCR analysis of this variant has shown a disruption of the splice donor site of intron 18, resulting in exon 18 skipping, which creates a transcript with an in-frame deletion of 42 base pairs (Horinouchi, 2018). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

X-linked Alport syndrome Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 06/18/2018 by GTR ID The Hospital for Sick Children. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104886314; hg19: chrX-107827755;