Genetic Variant NM_003057.3:c.169G>A (chr6-160122104-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003057.3(SLC22A1):c.169G>A(p.Glu57Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC22A1
NM_003057.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.01

Variant links:

Genes affected

SLC22A1 (HGNC:10963): (solute carrier family 22 member 1) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. This gene is one of three similar cation transporter genes located in a cluster on chromosome 6. The encoded protein contains twelve putative transmembrane domains and is a plasma integral membrane protein. Two transcript variants encoding two different isoforms have been found for this gene, but only the longer variant encodes a functional transporter. [provided by RefSeq, Jul 2008]

SLC22A1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A1	NM_003057.3 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 1 of 11	ENST00000366963.9	NP_003048.1	O15245-1
SLC22A1	NM_153187.2 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 1 of 10		NP_694857.1	O15245-2
SLC22A1	XM_005267103.3 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 1 of 12		XP_005267160.1
SLC22A1	XM_006715552.3 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 1 of 9		XP_006715615.1	O15245-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A1	ENST00000366963.9 link	c.169G>A	p.Glu57Lys	missense_variant	Exon 1 of 11	1	NM_003057.3	ENSP00000355930.4		O15245-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251202

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169G>A (p.E57K) alteration is located in exon 1 (coding exon 1) of the SLC22A1 gene. This alteration results from a G to A substitution at nucleotide position 169, causing the glutamic acid (E) at amino acid position 57 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

M;M;M;M

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

D;.;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.045

D;.;D;D

Sift4G

Uncertain

0.023

D;.;D;D

Polyphen

0.49

P;P;P;.

Vest4

0.68

MutPred

0.55

Gain of ubiquitination at E57 (P = 0.0219);Gain of ubiquitination at E57 (P = 0.0219);Gain of ubiquitination at E57 (P = 0.0219);Gain of ubiquitination at E57 (P = 0.0219);

MVP

0.42

MPC

0.39

ClinPred

0.99

GERP RS

4.6

Varity_R

0.54

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over