20-49839541-G-T

Variant names:

• chr20-49839541-G-T
• rs1412271501
• NM_015266.3:c.290G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015266.3(SLC9A8):​c.290G>T​(p.Gly97Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 16/26 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. G97D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLC9A8 NM_015266.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.33
• Publications: 0 publications found

Genes affected

SLC9A8 (HGNC:20728): (solute carrier family 9 member A8) Sodium-hydrogen exchangers (NHEs), such as SLC9A8, are integral transmembrane proteins that exchange extracellular Na+ for intracellular H+. NHEs have multiple functions, including intracellular pH homeostasis, cell volume regulation, and electroneutral NaCl absorption in epithelia (Xu et al., 2008 [PubMed 18209477]).[supplied by OMIM, Apr 2009]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015266.3. 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
	SLC9A8	NM_015266.3	MANE Select	c.290G>T	p.Gly97Val	missense splice_region	Exon 4 of 16	NP_056081.1	Q9Y2E8-1
	SLC9A8	NM_001260491.2		c.290G>T	p.Gly97Val	missense splice_region	Exon 4 of 16	NP_001247420.1	Q9Y2E8-2
	SLC9A8	NR_048537.2		n.385G>T		splice_region non_coding_transcript_exon	Exon 4 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A8	ENST00000361573.3	TSL:1 MANE Select	c.290G>T	p.Gly97Val	missense splice_region	Exon 4 of 16	ENSP00000354966.2	Q9Y2E8-1
	SLC9A8	ENST00000851371.1		c.290G>T	p.Gly97Val	missense splice_region	Exon 4 of 17	ENSP00000521430.1
	SLC9A8	ENST00000417961.5	TSL:2	c.290G>T	p.Gly97Val	missense splice_region	Exon 4 of 16	ENSP00000416418.1	Q9Y2E8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386620 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 693452

African (AFR) AF: 0.00 AC: 0 AN: 31688

American (AMR) AF: 0.00 AC: 0 AN: 43146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39072

South Asian (SAS) AF: 0.00 AC: 0 AN: 82568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048754

Other (OTH) AF: 0.00 AC: 0 AN: 57718

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.85		Loss of helix (P = 0.0376)
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.93
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.53		Position offset: 0

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

Other links and lift over

dbSNP: rs1412271501; hg19: chr20-48456078;