16-67249024-G-T

Variant names:

• chr16-67249024-G-T
• rs781377833
• NM_004594.3:c.10G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004594.3(SLC9A5):​c.10G>T​(p.Ala4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,425,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: SLC9A5 NM_004594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.251
• Publications: 0 publications found

Genes affected

SLC9A5 (HGNC:11078): (solute carrier family 9 member A5) Predicted to enable potassium:proton antiporter activity and sodium:proton antiporter activity. Predicted to be involved in potassium ion transmembrane transport; regulation of intracellular pH; and sodium ion import across plasma membrane. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. Implicated in end stage renal disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112817675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004594.3. 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
	SLC9A5	NM_004594.3	MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 1 of 16	NP_004585.1	Q14940
	SLC9A5	NM_001323973.2		c.10G>T	p.Ala4Ser	missense	Exon 1 of 16	NP_001310902.1
	SLC9A5	NM_001323972.2		c.10G>T	p.Ala4Ser	missense	Exon 1 of 15	NP_001310901.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A5	ENST00000299798.16	TSL:1 MANE Select	c.10G>T	p.Ala4Ser	missense	Exon 1 of 16	ENSP00000299798.11	Q14940
	SLC9A5	ENST00000563723.5	TSL:1	n.48G>T		non_coding_transcript_exon	Exon 1 of 15
	SLC9A5	ENST00000564812.5	TSL:1	n.10G>T		non_coding_transcript_exon	Exon 1 of 15	ENSP00000455058.1	H3BNY2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151834 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000235 AC: 3 AN: 1273888 Hom.: 0 Cov.: 30 AF XY: 0.00000319 AC XY: 2 AN XY: 626984

African (AFR) AF: 0.00 AC: 0 AN: 25920

American (AMR) AF: 0.00 AC: 0 AN: 22218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21592

East Asian (EAS) AF: 0.00 AC: 0 AN: 27980

South Asian (SAS) AF: 0.00 AC: 0 AN: 67584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3670

European-Non Finnish (NFE) AF: 0.00000294 AC: 3 AN: 1022080

Other (OTH) AF: 0.00 AC: 0 AN: 51692

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74166

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.25
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.14
Sift	Benign	0.094	T
Sift4G	Benign	0.24	T
Polyphen		0.049	B
Vest4		0.076
MutPred		0.055		Gain of phosphorylation at A4 (P = 0.0273)
MVP		0.63
MPC		0.53
ClinPred		0.11	T
GERP RS		2.9
PromoterAI		0.11	Neutral
Varity_R		0.075
gMVP		0.40
Mutation Taster		=98/2	polymorphism

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: rs781377833; hg19: chr16-67282927;