rs2289491

Variant names:

• chr3-143266875-T-C
• rs2289491
• NM_173653.4:c.1765A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-143266875-T-C
• chr3-143266875-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173653.4(SLC9A9):​c.1765A>G​(p.Ile589Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,614,180 control chromosomes in the GnomAD database, including 998 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. I589T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (77 hom., cov: 32)
  • Exomes 𝑓: 0.033 (921 hom.)
• Consequence: SLC9A9 NM_173653.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.754
• Publications: 18 publications found

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
• autism spectrum disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017031431).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A9	NM_173653.4	c.1765A>G	p.Ile589Val	missense_variant	Exon 16 of 16	ENST00000316549.11	NP_775924.1
SLC9A9	XM_017006203.2	c.1414A>G	p.Ile472Val	missense_variant	Exon 15 of 15		XP_016861692.1
SLC9A9	XM_011512703.4	c.1117A>G	p.Ile373Val	missense_variant	Exon 13 of 13		XP_011511005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A9	ENST00000316549.11	c.1765A>G	p.Ile589Val	missense_variant	Exon 16 of 16	1	NM_173653.4	ENSP00000320246.6

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3594 AN: 152184 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00617

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.0618

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0357 AC: 8966 AN: 251364 AF XY: 0.0372

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0483

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.0325

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0340

Gnomad OTH exome AF: 0.0346

GnomAD4 exome AF: 0.0327 AC: 47852 AN: 1461878 Hom.: 921 Cov.: 31 AF XY: 0.0338 AC XY: 24546 AN XY: 727234

African (AFR) AF: 0.00424 AC: 142 AN: 33480

American (AMR) AF: 0.0458 AC: 2047 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 655 AN: 26136

East Asian (EAS) AF: 0.0234 AC: 928 AN: 39700

South Asian (SAS) AF: 0.0616 AC: 5311 AN: 86258

European-Finnish (FIN) AF: 0.0187 AC: 998 AN: 53420

Middle Eastern (MID) AF: 0.0390 AC: 225 AN: 5768

European-Non Finnish (NFE) AF: 0.0321 AC: 35671 AN: 1111998

Other (OTH) AF: 0.0310 AC: 1875 AN: 60394

GnomAD4 genome AF: 0.0236 AC: 3597 AN: 152302 Hom.: 77 Cov.: 32 AF XY: 0.0240 AC XY: 1788 AN XY: 74474

African (AFR) AF: 0.00616 AC: 256 AN: 41584

American (AMR) AF: 0.0272 AC: 417 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.0253 AC: 131 AN: 5170

South Asian (SAS) AF: 0.0621 AC: 299 AN: 4818

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0326 AC: 2219 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0317 Hom.: 347

Bravo AF: 0.0241

TwinsUK AF: 0.0313 AC: 116

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0283 AC: 243

ExAC AF: 0.0365 AC: 4432

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.0370

EpiControl AF: 0.0337

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.75
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.068
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.036
ClinPred		0.0072	T
GERP RS		4.5
Varity_R		0.035
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289491; hg19: chr3-142985717;