rs796053290

chrX-135998094-CTTTAT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001379110.1(SLC9A6):c.370-9_370-5del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC9A6 NM_001379110.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 3.11

Genes affected

SLC9A6 (HGNC:11079): (solute carrier family 9 member A6) This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant X-135998094-CTTTAT-C is Pathogenic according to our data. Variant chrX-135998094-CTTTAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 207248.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-135998094-CTTTAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.370-9_370-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.370-9_370-5del		splice_polypyrimidine_tract_variant, intron_variant		4	NM_001379110.1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Christianson syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 19, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Feb 18, 2022	The c.430-9_430-5del variant in SLC9A6 occurs in the de novo state (biological parentage confirmed) in an individual with delayed motor milestones and hypotonia (Baylor Genetics internal database)(PS2). RNA study has shown that this variant impacts splicing (PMID 27256868) (PS3). This variant has been reported to segregate in four informative meioses (PMID 27256868)(PP1_moderate). The c.430-9_430-5del variant in SLC9A6 has been observed in 2 unrelated families with Christianson syndrome (PMID 27256868, Baylor Genetics internal database) (PS4_supporting). The c.430-9_430-5del variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary The c.430-9_430-5del variant in SLC9A6 is classified as pathogenic for Christianson syndrome based on the ACMG/AMP criteria (PS2, PS3, PP1_moderate, PS4_supporting, PM2_supporting). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	ClinVar contains an entry for this variant (Variation ID: 207248). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 27256868). This variant is also known as c.526-9_526-5del. This variant has been observed in individual(s) with clinical features of SLC9A6-related conditions (PMID: 27256868). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the SLC9A6 gene. It does not directly change the encoded amino acid sequence of the SLC9A6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

The c.430-9_430-5delTTTTA intronic variant, located in intron 2 of the SLC9A6 gene, results from a deletion of 5 nucleotides within intron 2 of the SLC9A6 gene. This variant (described as c.526-9_526-5del) was originally reported in an individual with intellectual disability (Redin C et al. J. Med. Genet., 2014 Nov;51:724-36). In the follow-up study, this individual was described to have mild intellectual disability, microcephaly, and social interaction disabilities, and the same variant was detected in his affected maternal uncle, as well as female family members with learning disabilities and speech difficulties (Masurel-Paulet A et al. Am. J. Med. Genet. A, 2016 Aug;170:2103-10). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site. Analysis of RNA from the proband's blood revealed that the intronic deletion results in the skipping of exon 3 in about 90% of the transcripts, leading to in-frame deletion of 26 amino acids in the TM4 domain (Masurel-Paulet A et al. Am. J. Med. Genet. A, 2016 Aug;170:2103-10). In addition, this variant was not reported in the gnomAD database, with coverage at this position. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Jul 25, 2014

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2015

The c.430-(9_5)delTTTTA variant has been previously reported (using alternative nomenclature of c.526-9_526-5delTTTTA), as a maternally inherited variant in an male patient (Redin et al., 2014). Several in-silico splice prediction models predict that c.430-(9_5)delTTTTA may damage or even destroy the natural splice acceptor site in intron 2, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs796053290; hg19: chrX-135080253;