5-476619-C-A

Variant names:

• chr5-476619-C-A
• rs146547322
• NM_004174.4:c.1814G>T

Variant summary

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

The NM_004174.4(SLC9A3):​c.1814G>T​(p.Arg605Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R605Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC9A3 NM_004174.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52
• Publications: 4 publications found

Genes affected

SLC9A3 (HGNC:11073): (solute carrier family 9 member A3) The protein encoded by this gene is an epithelial brush border Na/H exchanger that uses an inward sodium ion gradient to expel acids from the cell. Defects in this gene are a cause of congenital secretory sodium diarrhea. Pseudogenes of this gene exist on chromosomes 10 and 22. [provided by RefSeq, Mar 2016]

SLC9A3-AS1 (HGNC:40550): (SLC9A3 antisense RNA 1)

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=0.14785123).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004174.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A3	NM_004174.4	MANE Select	c.1814G>T	p.Arg605Leu	missense	Exon 12 of 17	NP_004165.2
	SLC9A3	NM_001284351.3		c.1787G>T	p.Arg596Leu	missense	Exon 12 of 17	NP_001271280.1
	SLC9A3-AS1	NR_125375.1		n.679+56C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A3	ENST00000264938.8	TSL:1 MANE Select	c.1814G>T	p.Arg605Leu	missense	Exon 12 of 17	ENSP00000264938.3
	SLC9A3	ENST00000514375.1	TSL:1	c.1787G>T	p.Arg596Leu	missense	Exon 12 of 17	ENSP00000422983.1
	SLC9A3	ENST00000644203.1		c.1814G>T	p.Arg605Leu	missense	Exon 12 of 16	ENSP00000495903.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246780 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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.24	N
REVEL	Uncertain	0.35
Sift	Benign	0.40	T
Sift4G	Benign	0.74	T
Polyphen		0.49	P
Vest4		0.61
MutPred		0.37		Loss of disorder (P = 0.0488)
MVP		0.73
MPC		0.52
ClinPred		0.70	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.16
gMVP		0.40
Mutation Taster		=84/16	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: rs146547322; hg19: chr5-476734;