NM_003060.4:c.-77G>A

Variant names:

• chr5-132369896-G-A
• rs13180295
• NM_003060.4:c.-77G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003060.4(SLC22A5):​c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0792 in 1,563,670 control chromosomes in the GnomAD database, including 6,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (576 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5571 hom.)
• Consequence: SLC22A5 NM_003060.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.425

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]

MIR3936HG (HGNC:40538): (MIR3936 host gene)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-132369896-G-A is Benign according to our data. Variant chr5-132369896-G-A is described in ClinVar as [Benign]. Clinvar id is 25343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132369896-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.-77G>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407	c.-77G>A		5_prime_UTR_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11686 AN: 152136 Hom.: 579 Cov.: 33

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0495

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.0650

Gnomad FIN AF: 0.0748

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.0755

GnomAD4 exome AF: 0.0794 AC: 112084 AN: 1411424 Hom.: 5571 Cov.: 30 AF XY: 0.0789 AC XY: 55178 AN XY: 699548

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.0539

Gnomad4 FIN exome AF: 0.0769

Gnomad4 NFE exome AF: 0.0750

Gnomad4 OTH exome AF: 0.0819

GnomAD4 genome AF: 0.0768 AC: 11685 AN: 152246 Hom.: 576 Cov.: 33 AF XY: 0.0759 AC XY: 5645 AN XY: 74418

Gnomad4 AFR AF: 0.0617

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.0648

Gnomad4 FIN AF: 0.0748

Gnomad4 NFE AF: 0.0767

Gnomad4 OTH AF: 0.0757

Alfa AF: 0.0770 Hom.: 63

Bravo AF: 0.0746

Asia WGS AF: 0.124 AC: 429 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal carnitine transport defect Benign:3

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Apr 19, 2018

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 18, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC22A5 c.-77G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.08 in 31310 control chromosomes in the gnomAD database, including 117 homozygotes. The observed variant frequency is approximately 17.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency phenotype (0.0046), strongly suggesting that the variant is benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Jun 23, 2018

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	-0.75
CADD	Benign	7.6
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs13180295; hg19: chr5-131705588;