rs11568513

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2

The NM_003060.4(SLC22A5):c.1441G>A(p.Val481Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,932 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V481F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 4 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 2.95

Variant links:

Genes affected

SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) 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. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_003060.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132392606-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.01349479).

BP6

Variant 5-132392606-G-A is Benign according to our data. Variant chr5-132392606-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 380141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4 linkuse as main transcript	c.1441G>A	p.Val481Ile	missense_variant	8/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8 linkuse as main transcript	c.1441G>A	p.Val481Ile	missense_variant	8/10	1	NM_003060.4	P1	O76082-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000708

AC:

178

AN:

251254

Hom.:

AF XY:

0.000773

AC XY:

105

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.000740

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00107

AC:

1564

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

764

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00218

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152260

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000908

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000766

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Renal carnitine transport defect

Uncertain:3Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 27, 2021	ACMG classification criteria: BP4 supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	This variant is associated with the following publications: (PMID: 16931768, 29406958) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -

SLC22A5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.48

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.13

Sift

Benign

0.41

T;T

Sift4G

Benign

0.91

T;T

Polyphen

0.0020

B;.

Vest4

0.053

MVP

0.63

MPC

0.17

ClinPred

0.0082

GERP RS

1.0

Varity_R

0.041

gMVP

0.42

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