chrX-135985518-T-A

Variant names:

• chrX-135985518-T-A
• ENST00000370695.8:c.16T>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001042537.2(SLC9A6):​c.16T>A​(p.Trp6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,006,294 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000020 (0 hom. 2 hem.)
• Consequence: SLC9A6 NM_001042537.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.12

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2507657).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.-57+41T>A		intron_variant	Intron 1 of 17	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000370695.8	c.16T>A	p.Trp6Arg	missense_variant	Exon 1 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.16T>A	p.Trp6Arg	missense_variant	Exon 1 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000630721.3	c.-57+41T>A		intron_variant	Intron 1 of 17	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370701.6	c.-57+41T>A		intron_variant	Intron 1 of 16	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000199 AC: 2 AN: 1006294 Hom.: 0 Cov.: 30 AF XY: 0.00000633 AC XY: 2 AN XY: 315772

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: 0.00000249

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Feb 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Christianson syndrome Uncertain:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 6 of the SLC9A6 protein (p.Trp6Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC9A6-related conditions. ClinVar contains an entry for this variant (Variation ID: 2574892). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.14	.;T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.51	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.0070	B;B
Vest4		0.29
MutPred		0.32		Gain of methylation at W6 (P = 0.002);Gain of methylation at W6 (P = 0.002);
MVP		0.37
MPC		1.7
ClinPred		0.26	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.41
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-135067677;