rs1553175089

Positions:

• chr1-27106019-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_003047.5(SLC9A1):​c.1351A>C​(p.Ile451Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I451I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC9A1 NM_003047.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP5: Variant 1-27106019-T-G is Pathogenic according to our data. Variant chr1-27106019-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A1	NM_003047.5	c.1351A>C	p.Ile451Leu	missense_variant	5/12	ENST00000263980.8
SLC9A1	XM_011542021.4	c.1021A>C	p.Ile341Leu	missense_variant	6/13
SLC9A1	XM_047428769.1	c.1021A>C	p.Ile341Leu	missense_variant	9/16
SLC9A1	NR_046474.2	n.1681A>C		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A1	ENST00000263980.8	c.1351A>C	p.Ile451Leu	missense_variant	5/12	1	NM_003047.5	P1
SLC9A1	ENST00000374086.3	c.1351A>C	p.Ile451Leu	missense_variant	5/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.053	T;D
Polyphen		0.99	D;D
Vest4		0.65
MutPred		0.56		Gain of catalytic residue at I451 (P = 0.0129);Gain of catalytic residue at I451 (P = 0.0129);
MVP		0.30
MPC		1.6
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.67
gMVP		0.91

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: rs1553175089; hg19: chr1-27432510;