5-132370237-A-G

Variant names:

• chr5-132370237-A-G
• rs765849408
• NM_003060.4:c.265A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003060.4(SLC22A5):​c.265A>G​(p.Ile89Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000704 in 1,421,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I89I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 1.04
• Publications: 0 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094341695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.265A>G	p.Ile89Val	missense_variant	Exon 1 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.265A>G	p.Ile89Val	missense_variant	Exon 1 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000704 AC: 10 AN: 1421028 Hom.: 0 Cov.: 31 AF XY: 0.0000114 AC XY: 8 AN XY: 703438

African (AFR) AF: 0.00 AC: 0 AN: 32294

American (AMR) AF: 0.00 AC: 0 AN: 37684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25506

East Asian (EAS) AF: 0.00 AC: 0 AN: 36918

South Asian (SAS) AF: 0.00 AC: 0 AN: 81886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.00000823 AC: 9 AN: 1093736

Other (OTH) AF: 0.0000170 AC: 1 AN: 58950

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Renal carnitine transport defect Uncertain:2

Jan 21, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SLC22A5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with valine at codon 89 of the SLC22A5 protein (p.Ile89Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. -

Decreased circulating carnitine concentration Uncertain:1

Jan 21, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.070	N;N
PhyloP100		1.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.070
Sift	Benign	0.89	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	B;.
Vest4		0.026
MutPred		0.62		Gain of MoRF binding (P = 0.089);Gain of MoRF binding (P = 0.089);
MVP		0.67
MPC		0.18
ClinPred		0.053	T
GERP RS		2.2
PromoterAI		-0.10	Neutral
Varity_R		0.051
gMVP		0.59
Mutation Taster		=89/11	polymorphism

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: rs765849408; hg19: chr5-131705929;