Genetic Variant NM_003060.4:c.59T>C (chr5-132370031-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_003060.4(SLC22A5):c.59T>C(p.Leu20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L20H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.30

Publications

0 publications found

Variant links:

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 links:

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

MIR3936HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_003060.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC22A5	NM_003060.4	MANE Select	c.59T>C	p.Leu20Pro	missense	Exon 1 of 10	NP_003051.1
SLC22A5	NM_001308122.2		c.59T>C	p.Leu20Pro	missense	Exon 1 of 11	NP_001295051.1
MIR3936HG	NR_110997.1		n.-115A>G		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.59T>C	p.Leu20Pro	missense	Exon 1 of 10	ENSP00000245407.3
SLC22A5	ENST00000435065.7	TSL:1	c.59T>C	p.Leu20Pro	missense	Exon 1 of 11	ENSP00000402760.2
SLC22A5	ENST00000448810.6	TSL:1	n.59T>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461122

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111728

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.6

PhyloP100

2.3

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.70

Sift

Benign

0.11

Sift4G

Benign

0.095

Polyphen

0.90

Vest4

0.79

MutPred

0.82

Loss of stability (P = 0.0129)

MVP

0.98

MPC

0.73

ClinPred

0.94

GERP RS

5.2

PromoterAI

0.067

Neutral

(source)

Varity_R

0.82

gMVP

0.96

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over