rs1553175089

Variant names:

• chr1-27106019-T-G
• rs1553175089
• NM_003047.5:c.1351A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Lichtenstein-Knorr syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 520778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC9A1	NM_003047.5	c.1351A>C	p.Ile451Leu	missense_variant	Exon 5 of 12	ENST00000263980.8	NP_003038.2
SLC9A1	XM_011542021.4	c.1021A>C	p.Ile341Leu	missense_variant	Exon 6 of 13		XP_011540323.1
SLC9A1	XM_047428769.1	c.1021A>C	p.Ile341Leu	missense_variant	Exon 9 of 16		XP_047284725.1
SLC9A1	NR_046474.2	n.1681A>C		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC9A1	ENST00000263980.8	c.1351A>C	p.Ile451Leu	missense_variant	Exon 5 of 12	1	NM_003047.5	ENSP00000263980.3
SLC9A1	ENST00000374086.3	c.1351A>C	p.Ile451Leu	missense_variant	Exon 5 of 5	1		ENSP00000363199.3

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

Oct 02, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		5.1
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
Mutation Taster		=32/68	disease causing (ClinVar)

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: rs1553175089; hg19: chr1-27432510;