rs188072063

chrX-136040072-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379110.1(SLC9A6):c.1662-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,197,139 control chromosomes in the GnomAD database, including 45 homozygotes. There are 4,024 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (4 hom., 221 hem., cov: 24)
  • Exomes 𝑓: 0.011 (41 hom. 3803 hem.)
• Consequence: SLC9A6 NM_001379110.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006198
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.23

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-136040072-G-A is Benign according to our data. Variant chrX-136040072-G-A is described in ClinVar as [Benign]. Clinvar id is 139208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136040072-G-A is described in Lovd as [Benign]. Variant chrX-136040072-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.1662-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1662-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		4	NM_001379110.1

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 787 AN: 112050 Hom.: 4 Cov.: 24 AF XY: 0.00646 AC XY: 221 AN XY: 34234

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.00313

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00665

GnomAD3 exomes AF: 0.00631 AC: 1124 AN: 178130 Hom.: 4 AF XY: 0.00647 AC XY: 408 AN XY: 63088

Gnomad AFR exome AF: 0.000703

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00477

Gnomad FIN exome AF: 0.00404

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.0110 AC: 11910 AN: 1085033 Hom.: 41 Cov.: 28 AF XY: 0.0108 AC XY: 3803 AN XY: 351625

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00527

Gnomad4 FIN exome AF: 0.00435

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.00957

GnomAD4 genome AF: 0.00702 AC: 787 AN: 112106 Hom.: 4 Cov.: 24 AF XY: 0.00644 AC XY: 221 AN XY: 34300

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00943

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00523

Gnomad4 FIN AF: 0.00313

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00657

Alfa AF: 0.00904 Hom.: 72

Bravo AF: 0.00712

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2018	- -

Christianson syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.027
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.016
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: rs188072063; hg19: chrX-135122231;