Genetic Variant SLC9A9:p.Tyr569Cys (chr3-143268879-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_173653.4(SLC9A9):c.1706A>G(p.Tyr569Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y569F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC9A9
NM_173653.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.79

Publications

0 publications found

Variant links:

Genes affected

SLC9A9 (HGNC:20653): (solute carrier family 9 member A9) This gene encodes a sodium/proton exchanger that is a member of the solute carrier 9 protein family. The encoded protein localizes the to the late recycling endosomes and may play an important role in maintaining cation homeostasis. Mutations in this gene are associated with autism susceptibility 16 and attention-deficit/hyperactivity disorder. [provided by RefSeq, Mar 2012]

SLC9A9 Gene-Disease associations (from GenCC):

autism, susceptibility to, 16
Inheritance: AD Classification: LIMITED Submitted by: G2P, PanelApp Australia
autism spectrum disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SLC9A9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173653.4. 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
	SLC9A9	NM_173653.4	MANE Select	c.1706A>G	p.Tyr569Cys	missense	Exon 15 of 16	NP_775924.1	Q8IVB4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A9	ENST00000316549.11	TSL:1 MANE Select	c.1706A>G	p.Tyr569Cys	missense	Exon 15 of 16	ENSP00000320246.6	Q8IVB4
	SLC9A9	ENST00000900956.1		c.1355A>G	p.Tyr452Cys	missense	Exon 12 of 13	ENSP00000571015.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448482

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33052

American (AMR)

AF:

0.00

AC:

AN:

44264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25636

East Asian (EAS)

AF:

0.00

AC:

AN:

38734

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102868

Other (OTH)

AF:

0.00

AC:

AN:

59396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.7

PhyloP100

5.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.32

Sift

Uncertain

0.020

Sift4G

Uncertain

0.053

Polyphen

1.0

Vest4

0.86

MutPred

0.31

Gain of glycosylation at Y569 (P = 0.0053)

MVP

0.88

MPC

0.32

ClinPred

0.99

GERP RS

4.4

Varity_R

0.40

gMVP

0.63

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over