X-108159457-C-A

Position:

• chrX-108159457-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033641.4(COL4A6):​c.4812+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000000911 in 1,097,893 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A6 NM_033641.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

COL4A6 (HGNC:2208): (collagen type IV alpha 6 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. 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, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.4812+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.4812+5G>T		splice_donor_5th_base_variant, intron_variant		5	NM_033641.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097893 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363285

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 17, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with COL4A6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 44 of the COL4A6 gene. It does not directly change the encoded amino acid sequence of the COL4A6 protein. It affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.42		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs2033844355; hg19: chrX-107402687;