X-135985510-G-A

Variant names:

• chrX-135985510-G-A
• rs1016216648
• ENST00000370695.8:c.8G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001438742.1(SLC9A6):​c.8G>A​(p.Arg3Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000202 in 990,223 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000020 (0 hom. 1 hem.)
• Consequence: SLC9A6 NM_001438742.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.608
• Publications: 0 publications found

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]

SLC9A6 Gene-Disease associations (from GenCC):

• Christianson syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.131311).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438742.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	NM_001379110.1	MANE Select	c.-57+33G>A		intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.8G>A	p.Arg3Gln	missense	Exon 1 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.8G>A	p.Arg3Gln	missense	Exon 1 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000370695.8	TSL:1	c.8G>A	p.Arg3Gln	missense	Exon 1 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.8G>A	p.Arg3Gln	missense	Exon 1 of 16	ENSP00000359732.3	Q92581-1
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+33G>A		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000202 AC: 2 AN: 990223 Hom.: 0 Cov.: 30 AF XY: 0.00000322 AC XY: 1 AN XY: 310275

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22515

American (AMR) AF: 0.00 AC: 0 AN: 20657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14862

East Asian (EAS) AF: 0.00 AC: 0 AN: 25848

South Asian (SAS) AF: 0.00 AC: 0 AN: 41911

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2746

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 794121

Other (OTH) AF: 0.0000239 AC: 1 AN: 41877

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.61
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.020
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.20	B
Vest4		0.20
MutPred		0.29		Gain of relative solvent accessibility (P = 0.09)
MVP		0.12
MPC		1.2
ClinPred		0.33	T
GERP RS		1.6
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.041
gMVP		0.54
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1016216648; hg19: chrX-135067669;