rs104886431

Variant names:

• chrX-108575909-G-A
• rs104886431
• NM_033380.3:c.547-1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_033380.3(COL4A5):​c.547-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.09
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012411348 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.6, offset of 1, new splice context is: tttactcactttataacaAGgcc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108575909-G-A is Pathogenic according to our data. Variant chrX-108575909-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2627802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.547-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.547-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.547-1G>A		splice_acceptor_variant, intron_variant	Intron 9 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1051761 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 327059

African (AFR) AF: 0.00 AC: 0 AN: 25408

American (AMR) AF: 0.00 AC: 0 AN: 34729

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18968

East Asian (EAS) AF: 0.00 AC: 0 AN: 29647

South Asian (SAS) AF: 0.00 AC: 0 AN: 52027

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 802551

Other (OTH) AF: 0.00 AC: 0 AN: 44465

GnomAD4 genome Cov.: 23

Alfa AF: 0.00155 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 9 of the COL4A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 11462238, 20378821). This variant is also known as c.749-1G>A. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

X-linked Alport syndrome Pathogenic:1

Sep 05, 2022

Medical Genetics Department, Charles Nicolle Hospital Tunis

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequencing revealed a novel hemizygous splicing mutation, NM_000495: c.547-1G>A, in three males from a Tunisian family. This splicing mutation, NM_000495: c.547-1G>A, was not found in the NHLBI Exome Variant Server or the ClinVar database. Analysis of NM_000495: c.547-1G>A using Alamut predicted a highly probable exon 10 skipping. The segregation pattern is consistent with an X-linked dominant mode. Notably, this novel mutation was absent in 50 control Tunisian samples. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.1
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.46		Position offset: 2
DS_AL_spliceai		0.96		Position offset: 1

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

Other links and lift over

dbSNP: rs104886431; hg19: chrX-107819139;