Genetic Variant NM_003057.3:c.524G>T (chr6-160132240-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003057.3(SLC22A1):c.524G>T(p.Arg175Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SLC22A1
NM_003057.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.55

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A1	NM_003057.3 link	c.524G>T	p.Arg175Leu	missense_variant	Exon 3 of 11	ENST00000366963.9	NP_003048.1	O15245-1
SLC22A1	NM_153187.2 link	c.524G>T	p.Arg175Leu	missense_variant	Exon 3 of 10		NP_694857.1	O15245-2
SLC22A1	XM_005267103.3 link	c.524G>T	p.Arg175Leu	missense_variant	Exon 3 of 12		XP_005267160.1
SLC22A1	XM_006715552.3 link	c.524G>T	p.Arg175Leu	missense_variant	Exon 3 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.524G>T	p.Arg175Leu	missense_variant	Exon 3 of 11	1	NM_003057.3	ENSP00000355930.4		O15245-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000441

AC:

AN:

226988

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122498

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426458

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524G>T (p.R175L) alteration is located in exon 3 (coding exon 3) of the SLC22A1 gene. This alteration results from a G to T substitution at nucleotide position 524, causing the arginine (R) at amino acid position 175 to be replaced by a leucine (L). 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

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.3

H;H;H;H

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.4

D;.;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.99

MutPred

0.72

Gain of methylation at R172 (P = 0.0843);Gain of methylation at R172 (P = 0.0843);Gain of methylation at R172 (P = 0.0843);Gain of methylation at R172 (P = 0.0843);

MVP

0.64

MPC

0.67

ClinPred

1.0

GERP RS

4.3

Varity_R

0.95

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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