rs274558

Variant names:

• chr5-132385482-A-G
• rs274558
• NM_003060.4:c.807A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003060.4(SLC22A5):​c.807A>G​(p.Leu269Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,282 control chromosomes in the GnomAD database, including 137,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L269L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13083 hom., cov: 33)
  • Exomes 𝑓: 0.40 (124757 hom.)
• Consequence: SLC22A5 NM_003060.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.264
• Publications: 50 publications found

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 Gene-Disease associations (from GenCC):

• systemic primary carnitine deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• short QT syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 5-132385482-A-G is Benign according to our data. Variant chr5-132385482-A-G is described in ClinVar as Benign. ClinVar VariationId is 94101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.264 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.807A>G	p.Leu269Leu	synonymous_variant	Exon 4 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.807A>G	p.Leu269Leu	synonymous_variant	Exon 4 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61672 AN: 151926 Hom.: 13075 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.435 AC: 109359 AN: 251282 AF XY: 0.448

Gnomad AFR exome AF: 0.357

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.643

Gnomad FIN exome AF: 0.509

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.404 AC: 591038 AN: 1461238 Hom.: 124757 Cov.: 41 AF XY: 0.412 AC XY: 299529 AN XY: 726990

African (AFR) AF: 0.354 AC: 11847 AN: 33472

American (AMR) AF: 0.325 AC: 14529 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10465 AN: 26136

East Asian (EAS) AF: 0.668 AC: 26506 AN: 39688

South Asian (SAS) AF: 0.621 AC: 53552 AN: 86254

European-Finnish (FIN) AF: 0.505 AC: 26976 AN: 53406

Middle Eastern (MID) AF: 0.471 AC: 2713 AN: 5764

European-Non Finnish (NFE) AF: 0.377 AC: 419332 AN: 1111434

Other (OTH) AF: 0.416 AC: 25118 AN: 60374

GnomAD4 genome AF: 0.406 AC: 61712 AN: 152044 Hom.: 13083 Cov.: 33 AF XY: 0.417 AC XY: 30987 AN XY: 74306

African (AFR) AF: 0.359 AC: 14881 AN: 41452

American (AMR) AF: 0.352 AC: 5384 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1443 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3458 AN: 5162

South Asian (SAS) AF: 0.642 AC: 3096 AN: 4824

European-Finnish (FIN) AF: 0.512 AC: 5411 AN: 10564

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26854 AN: 67956

Other (OTH) AF: 0.391 AC: 828 AN: 2116

Alfa AF: 0.387 Hom.: 30713

Bravo AF: 0.385

Asia WGS AF: 0.617 AC: 2144 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.376

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Benign:7

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Dec 07, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Apr 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.807A>G variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. Mutatation Taster predicts polymorphism outcome for this variant. 5/5 splice-site tools via Alamut predict that this variant does not affect the consensus splice donor site though it may create a cryptic splice donor site as predicted by 3/5 tools. However, in silico prediction results are not definite and there are no functional studies to confirm this. This variant is found in 53257/121244 control chromosomes (12476 homozygotes) from the large and broad populations of ExAC at a frequency of 0.4392547, which is about 96 times greater than the maximal expected frequency of a pathogenic allele (0.0045644) in this gene. Thus this variant is a common polymorphism found in general population. In one family, this variant was found in cis with a potentially pathogenic variant p.Leu476Arg in homozygous state in two affected siblings and was found in homozygous state in the unaffected father of the siblings (Mutlu-Albayrak_2015) -- an evidence of lack of cosegregation which further supports the benign outcome. One clinical laboratory has classified this variant as benign. Taken together, this variant has been classified as Benign. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.1
DANN	Benign	0.53
PhyloP100		-0.26
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs274558; hg19: chr5-131721174; COSMIC: COSV55373003; COSMIC: COSV55373003;