X-135985504-T-A

Variant summary

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

The ENST00000370695.8(SLC9A6):c.2T>A(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 0.00000814 in 982,839 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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: 0.0000081 (0 hom. 4 hem.)
• Consequence: SLC9A6 ENST00000370695.8 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>A		intron_variant		ENST00000630721.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000814 AC: 8 AN: 982839 Hom.: 0 Cov.: 29 AF XY: 0.0000130 AC XY: 4 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: 0.0000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

GeneDx

Apr 28, 2022

Not observed in large population cohorts (gnomAD); 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	0.63	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	19
Dann	Benign	0.96
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.94	D;D;D
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0050	B;B
Vest4		0.73
MutPred		0.84		Gain of ubiquitination at M1 (P = 0.0428);Gain of ubiquitination at M1 (P = 0.0428);
MVP		0.98
ClinPred		0.95	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs1006154022; hg19: chrX-135067663;