X-135985504-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The ENST00000370695.8(SLC9A6):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 982,839 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000017 (0 hom. 5 hem.)
• Consequence: SLC9A6 ENST00000370695.8 start_lost
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 1.01

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.

• PVS1: Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.-57+27T>G		intron_variant		ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.-57+27T>G		intron_variant		4	NM_001379110.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000202 AC: 1 AN: 49564 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 7026

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 17 AN: 982839 Hom.: 0 Cov.: 29 AF XY: 0.0000162 AC XY: 5 AN XY: 308177

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000215

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Christianson syndrome Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 24, 2021	The p.Met1? variant in SLC9A6 may cause a truncated or absent protein by altering the start codon of the coding sequence, however, to date, there is no additional evidence to support that the loss of this methionine is associated with disease (PVS1_supporting). The p.Met1? variant in SLC9A6 is absent from gnomAD (PM2_supporting). In summary, the p.Met1? variant in SLC9A6 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PVS1_supporting, PM2_supporting). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change affects the initiator methionine of the SLC9A6 mRNA. The next in-frame methionine is located at codon 25. This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. Disruption of the initiator codon has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 383439). This variant disrupts a region of the SLC9A6 protein in which other variant(s) (p.Arg13His) have been observed in individuals with SLC9A6-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The c.2T>G (p.M1?) alteration is located in coding exon 1 of the SLC9A6 gene and consists of a T to G substitution at nucleotide position 1. This changes the amino acid from a methionine to a (?) at the initiation codon. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2022

Initiation codon variant in a region of a gene for which loss of function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	19
Dann	Benign	0.97
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.96	D;D;D
PROVEAN	Benign	-0.22	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.77
MutPred		0.86		Gain of methylation at M1 (P = 0.031);Gain of methylation at M1 (P = 0.031);
MVP		0.97
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1006154022; hg19: chrX-135067663;