1-27100480-C-T

Position:

• chr1-27100480-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003047.5(SLC9A1):​c.2275G>A​(p.Asp759Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SLC9A1 NM_003047.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.08

Genes affected

SLC9A1 (HGNC:11071): (solute carrier family 9 member A1) This gene encodes a Na+/H+ antiporter that is a member of the solute carrier family 9. The encoded protein is a plasma membrane transporter that is expressed in the kidney and intestine. This protein plays a central role in regulating pH homeostasis, cell migration and cell volume. This protein may also be involved in tumor growth. [provided by RefSeq, Sep 2011]

SLC9A1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC9A1. . Gene score misZ 3.5504 (greater than the threshold 3.09). Trascript score misZ 4.6807 (greater than threshold 3.09). GenCC has associacion of gene with Lichtenstein-Knorr syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.108653605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC9A1	NM_003047.5	c.2275G>A	p.Asp759Asn	missense_variant	12/12	ENST00000263980.8	NP_003038.2
SLC9A1	XM_011542021.4	c.1945G>A	p.Asp649Asn	missense_variant	13/13		XP_011540323.1
SLC9A1	XM_047428769.1	c.1945G>A	p.Asp649Asn	missense_variant	16/16		XP_047284725.1
SLC9A1	NR_046474.2	n.2605G>A		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC9A1	ENST00000263980.8	c.2275G>A	p.Asp759Asn	missense_variant	12/12	1	NM_003047.5	ENSP00000263980.3
SLC9A1	ENST00000374089.5	n.1500G>A		non_coding_transcript_exon_variant	7/7	2
SLC9A1	ENST00000447808.1	n.752G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251366 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135842

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000405

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461782 Hom.: 0 Cov.: 38 AF XY: 0.000286 AC XY: 208 AN XY: 727206

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000336

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152194 Hom.: 0 Cov.: 34 AF XY: 0.000390 AC XY: 29 AN XY: 74346

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.2275G>A (p.D759N) alteration is located in exon 12 (coding exon 12) of the SLC9A1 gene. This alteration results from a G to A substitution at nucleotide position 2275, causing the aspartic acid (D) at amino acid position 759 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 05, 2024

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.13
Sift	Benign	0.073	T
Sift4G	Benign	0.42	T
Polyphen		0.91	P
Vest4		0.19
MVP		0.32
MPC		0.41
ClinPred		0.030	T
GERP RS		4.2
Varity_R		0.056
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs140504210; hg19: chr1-27426971; COSMIC: COSV56056641; COSMIC: COSV56056641;