rs180727016

Variant names:

• chrX-136024487-A-G
• rs180727016
• NM_001379110.1:c.1460+4A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379110.1(SLC9A6):​c.1460+4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,193,640 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,255 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 0.0023 (0 hom., 85 hem., cov: 23)
  • Exomes 𝑓: 0.0032 (6 hom. 1170 hem.)
• Consequence: SLC9A6 NM_001379110.1 splice_region, intron
• Scores: Splicing: ADA: 0.009188
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.991

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant X-136024487-A-G is Benign according to our data. Variant chrX-136024487-A-G is described in ClinVar as [Benign]. Clinvar id is 95376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136024487-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (259/111845) while in subpopulation NFE AF= 0.00327 (174/53232). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 85 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.1460+4A>G		splice_region_variant, intron_variant	Intron 13 of 17	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.1460+4A>G		splice_region_variant, intron_variant	Intron 13 of 17	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.1616+4A>G		splice_region_variant, intron_variant	Intron 12 of 15	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.1520+4A>G		splice_region_variant, intron_variant	Intron 12 of 15	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.1460+4A>G		splice_region_variant, intron_variant	Intron 13 of 16	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 259 AN: 111793 Hom.: 0 Cov.: 23 AF XY: 0.00250 AC XY: 85 AN XY: 33961

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00327

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00261 AC: 478 AN: 183114 Hom.: 1 AF XY: 0.00293 AC XY: 198 AN XY: 67600

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00325

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00316 AC: 3423 AN: 1081795 Hom.: 6 Cov.: 28 AF XY: 0.00336 AC XY: 1170 AN XY: 347829

Gnomad4 AFR exome AF: 0.000115

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00341

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00232 AC: 259 AN: 111845 Hom.: 0 Cov.: 23 AF XY: 0.00250 AC XY: 85 AN XY: 34023

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.000477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000750

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.00327

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00192 Hom.: 15

Bravo AF: 0.00136

EpiCase AF: 0.00235

EpiControl AF: 0.00339

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Aug 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 11, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Christianson syndrome Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 14, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

SLC9A6-related disorder Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0092
dbscSNV1_RF	Benign	0.26
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: rs180727016; hg19: chrX-135106646;