chrX-135985823-T-G

Variant names:

• chrX-135985823-T-G
• rs797045973
• NM_001379110.1:c.165T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001379110.1(SLC9A6):​c.165T>G​(p.Ile55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I55V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SLC9A6 NM_001379110.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.161
• 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, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001379110.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A6	NM_001379110.1	c.165T>G	p.Ile55Met	missense_variant	Exon 2 of 18	ENST00000630721.3	NP_001366039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A6	ENST00000630721.3	c.165T>G	p.Ile55Met	missense_variant	Exon 2 of 18	4	NM_001379110.1	ENSP00000487486.2
SLC9A6	ENST00000370695.8	c.321T>G	p.Ile107Met	missense_variant	Exon 1 of 16	1		ENSP00000359729.4
SLC9A6	ENST00000370698.7	c.321T>G	p.Ile107Met	missense_variant	Exon 1 of 16	1		ENSP00000359732.3
SLC9A6	ENST00000370701.6	c.165T>G	p.Ile55Met	missense_variant	Exon 2 of 17	1		ENSP00000359735.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	.;.;.;.;.;.;.;T;T;.
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.87	.;.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;.;.;.;.;.;L;L;.;.
PhyloP100		-0.16
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	.;.;.;.;.;N;N;N;.;.
REVEL	Benign	0.16
Sift	Benign	0.031	.;.;.;.;.;D;D;D;.;.
Sift4G	Uncertain	0.022	.;.;.;.;.;D;D;D;D;.
Polyphen		0.84, 0.74	.;.;.;.;.;.;P;P;.;.
Vest4		0.42, 0.43, 0.42
MutPred		0.65		.;.;.;.;.;.;Loss of catalytic residue at I107 (P = 0.0018);Loss of catalytic residue at I107 (P = 0.0018);.;.;
MVP		0.20
MPC		1.3
ClinPred		0.73	D
GERP RS		1.9
PromoterAI		0.0035	Neutral
Varity_R		0.36
gMVP		0.90
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: -1
DS_DL_spliceai		0.29		Position offset: 4

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

Other links and lift over

dbSNP: rs797045973; hg19: chrX-135067982;