Genetic Variant SLC9A6:p.Ala9Thr (chrX-135985527-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000370695.8(SLC9A6):c.25G>A(p.Ala9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000981 in 1,019,734 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. A9S) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.8e-7 ( 0 hom. 1 hem. )

Consequence

SLC9A6
ENST00000370695.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.12

Publications

0 publications found

Variant links:

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, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen

SLC9A6 links:

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ACMG classification

Classification was made for transcript

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=0.1658698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1 link	c.-57+50G>A		intron_variant	Intron 1 of 17	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC9A6	ENST00000370695.8 link	c.25G>A	p.Ala9Thr	missense_variant	Exon 1 of 16	1		ENSP00000359729.4	Q92581-2
SLC9A6	ENST00000370698.7 link	c.25G>A	p.Ala9Thr	missense_variant	Exon 1 of 16	1		ENSP00000359732.3	Q92581-1
SLC9A6	ENST00000630721.3 link	c.-57+50G>A		intron_variant	Intron 1 of 17	4	NM_001379110.1	ENSP00000487486.2	A0A0D9SGH0
SLC9A6	ENST00000370701.6 link	c.-57+50G>A		intron_variant	Intron 1 of 16	1		ENSP00000359735.1	Q92581-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.81e-7

AC:

AN:

1019734

Hom.:

Cov.:

AF XY:

0.00000312

AC XY:

AN XY:

320410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23701

American (AMR)

AF:

0.00

AC:

AN:

25522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15932

East Asian (EAS)

AF:

0.00

AC:

AN:

27393

South Asian (SAS)

AF:

0.00

AC:

AN:

45254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3004

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

807135

Other (OTH)

AF:

0.0000233

AC:

AN:

42911

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.098

.;T

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PhyloP100

2.1

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.030

Sift

Benign

0.12

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.0050

B;B

Vest4

0.27

MutPred

0.24

Gain of phosphorylation at A9 (P = 0.0068);Gain of phosphorylation at A9 (P = 0.0068);

MVP

0.22

MPC

1.0

ClinPred

0.057

GERP RS

2.9

PromoterAI

0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.064

gMVP

0.29

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over