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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003057.3(SLC22A1):c.524G>A(p.Arg175His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000703 in 1,578,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

SLC22A1
NM_003057.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A1	NM_003057.3 link	c.524G>A	p.Arg175His	missense_variant	Exon 3 of 11	ENST00000366963.9	NP_003048.1	O15245-1
SLC22A1	NM_153187.2 link	c.524G>A	p.Arg175His	missense_variant	Exon 3 of 10		NP_694857.1	O15245-2
SLC22A1	XM_005267103.3 link	c.524G>A	p.Arg175His	missense_variant	Exon 3 of 12		XP_005267160.1
SLC22A1	XM_006715552.3 link	c.524G>A	p.Arg175His	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>A	p.Arg175His	missense_variant	Exon 3 of 11	1	NM_003057.3	ENSP00000355930.4		O15245-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

226988

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

122498

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000427

Gnomad SAS exome

AF:

0.0000391

Gnomad FIN exome

AF:

0.000429

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.000185

GnomAD4 exome

AF:

0.0000708

AC:

101

AN:

1426454

Hom.:

Cov.:

AF XY:

0.0000637

AC XY:

AN XY:

706710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000369

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.000473

Gnomad4 NFE exome

AF:

0.0000430

Gnomad4 OTH exome

AF:

0.000238

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000840

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

D;D;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;H;H;H

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.6

D;.;D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.99

MVP

0.55

MPC

0.67

ClinPred

0.72

GERP RS

4.3

Varity_R

0.90

gMVP

0.89

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over