rs149730454

chr5-132390779-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_003060.4(SLC22A5):c.1142T>C(p.Met381Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,614,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.29

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 Likely_benign. Variant got -1 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, 4 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0123618245).
• BP6: Variant 5-132390779-T-C is Benign according to our data. Variant chr5-132390779-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460391.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A5	NM_003060.4	c.1142T>C	p.Met381Thr	missense_variant	7/10	ENST00000245407.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A5	ENST00000245407.8	c.1142T>C	p.Met381Thr	missense_variant	7/10	1	NM_003060.4	P1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251482 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135914

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 727248

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74508

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000744 Hom.: 0

Bravo AF: 0.000536

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal carnitine transport defect Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	in vitro;research	Giacomini Lab, University of California, San Francisco	Oct 03, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Decreased circulating carnitine concentration Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	12
Dann	Benign	0.33
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.077
Sift	Benign	0.30	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	B;.
Vest4		0.27
MVP		0.44
MPC		0.24
ClinPred		0.0012	T
GERP RS		3.5
Varity_R		0.056
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149730454; hg19: chr5-131726471;