chr1-27100484-G-C

Variant names:

• chr1-27100484-G-C
• rs748647066
• NM_003047.5:c.2271C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003047.5(SLC9A1):​c.2271C>G​(p.Asp757Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D757D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC9A1 NM_003047.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.01
• Publications: 2 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022720128).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003047.5. 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
	SLC9A1	NM_003047.5	MANE Select	c.2271C>G	p.Asp757Glu	missense	Exon 12 of 12	NP_003038.2
	SLC9A1	NR_046474.2		n.2601C>G		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9A1	ENST00000263980.8	TSL:1 MANE Select	c.2271C>G	p.Asp757Glu	missense	Exon 12 of 12	ENSP00000263980.3	P19634-1
	SLC9A1	ENST00000854572.1		c.2271C>G	p.Asp757Glu	missense	Exon 13 of 13	ENSP00000524631.1
	SLC9A1	ENST00000854573.1		c.2106C>G	p.Asp702Glu	missense	Exon 12 of 12	ENSP00000524632.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251376 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461782 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.000262 AC: 4 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0010
DANN	Benign	0.52
DEOGEN2	Benign	0.22	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-6.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.022
Sift	Benign	0.45	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.065
MutPred		0.20		Loss of stability (P = 0.0636)
MVP		0.10
MPC		0.23
ClinPred		0.025	T
GERP RS		-8.1
Varity_R		0.020
gMVP		0.080
Mutation Taster		=95/5	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: rs748647066; hg19: chr1-27426975;