3-143268967-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_173653.4(SLC9A9):c.1618A>G(p.Ile540Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,280 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0072 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: SLC9A9 NM_173653.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00714314).
• BP6: Variant 3-143268967-T-C is Benign according to our data. Variant chr3-143268967-T-C is described in ClinVar as [Benign]. Clinvar id is 714208.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00721 (1098/152196) while in subpopulation AFR AF= 0.0253 (1052/41500). AF 95% confidence interval is 0.0241. There are 13 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1094 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A9	NM_173653.4	c.1618A>G	p.Ile540Val	missense_variant	15/16	ENST00000316549.11
SLC9A9	XM_017006203.2	c.1267A>G	p.Ile423Val	missense_variant	14/15
SLC9A9	XM_011512703.4	c.970A>G	p.Ile324Val	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A9	ENST00000316549.11	c.1618A>G	p.Ile540Val	missense_variant	15/16	1	NM_173653.4	P1

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1094 AN: 152078 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00184 AC: 463 AN: 251362 Hom.: 5 AF XY: 0.00136 AC XY: 185 AN XY: 135830

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000737 AC: 1077 AN: 1461084 Hom.: 12 Cov.: 31 AF XY: 0.000616 AC XY: 448 AN XY: 726858

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00721 AC: 1098 AN: 152196 Hom.: 13 Cov.: 32 AF XY: 0.00724 AC XY: 539 AN XY: 74406

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00151 Hom.: 6

Bravo AF: 0.00820

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.94	N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.10
Sift	Benign	0.17	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.43
MPC		0.037
ClinPred		0.010	T
GERP RS		4.5
Varity_R		0.095
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs16853300; hg19: chr3-142987809;