rs13180043

chr5-132369895-C-T

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.-78C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,557,066 control chromosomes in the GnomAD database, including 6,153 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: 0.080 (5577 hom.)
• Consequence: SLC22A5 NM_003060.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.434

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=-0.74).
• BP6: Variant 5-132369895-C-T is Benign according to our data. Variant chr5-132369895-C-T is described in ClinVar as [Benign]. Clinvar id is 25342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132369895-C-T 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/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.-78C>T		5_prime_UTR_variant	1/10	ENST00000245407.8
MIR3936HG	NR_110997.1	n.22G>A		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.-78C>T		5_prime_UTR_variant	1/10	1	NM_003060.4	P1
MIR3936HG	ENST00000621103.4	n.22G>A		non_coding_transcript_exon_variant	1/8	1

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11687 AN: 152144 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: 0.0649

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.0756

GnomAD4 exome AF: 0.0797 AC: 111940 AN: 1404812 Hom.: 5577 Cov.: 29 AF XY: 0.0792 AC XY: 55089 AN XY: 695708

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.0378

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.0544

Gnomad4 FIN exome AF: 0.0777

Gnomad4 NFE exome AF: 0.0751

Gnomad4 OTH exome AF: 0.0822

GnomAD4 genome AF: 0.0768 AC: 11686 AN: 152254 Hom.: 576 Cov.: 33 AF XY: 0.0758 AC XY: 5645 AN XY: 74430

Gnomad4 AFR AF: 0.0618

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.0647

Gnomad4 FIN AF: 0.0747

Gnomad4 NFE AF: 0.0767

Gnomad4 OTH AF: 0.0758

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 18, 2021

Variant summary: SLC22A5 c.-78C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.08 in 31322 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.9
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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

Other links and lift over

dbSNP: rs13180043; hg19: chr5-131705587;