rs10040427

chr5-132378414-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_003060.4(SLC22A5):c.430C>T(p.Leu144Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,614,242 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L144L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (103 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (128 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.325

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_003060.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0027811527).
• BP6: Variant 5-132378414-C-T is Benign according to our data. Variant chr5-132378414-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 25373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132378414-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.430C>T	p.Leu144Phe	missense_variant	2/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.430C>T	p.Leu144Phe	missense_variant	2/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3290 AN: 152250 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00579 AC: 1456 AN: 251494 Hom.: 50 AF XY: 0.00413 AC XY: 562 AN XY: 135920

Gnomad AFR exome AF: 0.0788

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00222 AC: 3252 AN: 1461874 Hom.: 128 Cov.: 31 AF XY: 0.00192 AC XY: 1393 AN XY: 727240

Gnomad4 AFR exome AF: 0.0767

Gnomad4 AMR exome AF: 0.00405

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.0216 AC: 3297 AN: 152368 Hom.: 103 Cov.: 32 AF XY: 0.0206 AC XY: 1538 AN XY: 74512

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.00568

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00394 Hom.: 42

Bravo AF: 0.0246

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0822 AC: 362

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00738 AC: 896

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Apr 09, 2014	- -

not specified Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:16931768). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.016	N
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.084
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.10	B;.;.
Vest4		0.18
MVP		0.84
MPC		0.33
ClinPred		0.0073	T
GERP RS		3.0
Varity_R		0.10
gMVP		0.72

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

Other links and lift over

dbSNP: rs10040427; hg19: chr5-131714106;