X-135985503-A-T

Variant names:

• chrX-135985503-A-T
• rs782640388
• ENST00000370695.8:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001438742.1(SLC9A6):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 982,421 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000051 (0 hom. 1 hem.)
• Consequence: SLC9A6 NM_001438742.1 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 1 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, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 25 codons. Genomic position: 135985575. Lost 0.033 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438742.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	NM_001379110.1	MANE Select	c.-57+26A>T		intron	N/A	NP_001366039.1	A0A0D9SGH0
	SLC9A6	NM_001438742.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 17	NP_001425671.1
	SLC9A6	NM_001042537.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 16	NP_001036002.1	Q92581-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A6	ENST00000370695.8	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 16	ENSP00000359729.4	Q92581-2
	SLC9A6	ENST00000370698.7	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 16	ENSP00000359732.3	Q92581-1
	SLC9A6	ENST00000630721.3	TSL:4 MANE Select	c.-57+26A>T		intron	N/A	ENSP00000487486.2	A0A0D9SGH0

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000206 AC: 1 AN: 48541 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000509 AC: 5 AN: 982421 Hom.: 0 Cov.: 29 AF XY: 0.00000324 AC XY: 1 AN XY: 308303

African (AFR) AF: 0.00 AC: 0 AN: 22085

American (AMR) AF: 0.00 AC: 0 AN: 19318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14540

East Asian (EAS) AF: 0.00 AC: 0 AN: 25599

South Asian (SAS) AF: 0.0000242 AC: 1 AN: 41270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2697

European-Non Finnish (NFE) AF: 0.00000506 AC: 4 AN: 790307

Other (OTH) AF: 0.00 AC: 0 AN: 41489

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000106 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.091	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.86
MutPred		0.83		Gain of stability (P = 0.1523)
MVP		0.96
ClinPred		0.80	D
GERP RS		4.9
PromoterAI		-0.23	Neutral
Varity_R		0.33
gMVP		0.60
Mutation Taster		=80/120	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782640388; hg19: chrX-135067662;