dbSNP rs28383481: SLC22A5:p.Arg488His (chr5-132393688-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 6P and 12B. PS3PM5BP4_StrongBS1BS2

The NM_003060.4(SLC22A5):c.1463G>A(p.Arg488His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,104 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000514640: When A142S and R488H were present on the same allele, expression in CHO cells showed significantly impaired carnitine transport, indicating that A142S and R488H need to be present on the same SLC22A5 allele in order to impair function (Amat di San Filippo et al., 2006).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 26 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:10B:4

Conservation

PhyloP100: 2.76

Publications

36 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 Gene-Disease associations (from GenCC):

systemic primary carnitine deficiency disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, ClinGen
short QT syndrome
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

SLC22A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000514640: When A142S and R488H were present on the same allele, expression in CHO cells showed significantly impaired carnitine transport, indicating that A142S and R488H need to be present on the same SLC22A5 allele in order to impair function (Amat di San Filippo et al., 2006).

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132393687-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 460399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.017382115).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00342 (520/152254) while in subpopulation AMR AF = 0.00713 (109/15298). AF 95% confidence interval is 0.00604. There are 1 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.1463G>A	p.Arg488His	missense	Exon 9 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.1535G>A	p.Arg512His	missense	Exon 10 of 11	NP_001295051.1	O76082-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.1463G>A	p.Arg488His	missense	Exon 9 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.1535G>A	p.Arg512His	missense	Exon 10 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.*315G>A		non_coding_transcript_exon	Exon 9 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00522

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00325

AC:

817

AN:

251442

AF XY:

0.00321

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00466

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00467

AC:

6834

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

3339

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33476

American (AMR)

AF:

0.00449

AC:

201

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00147

AC:

127

AN:

86258

European-Finnish (FIN)

AF:

0.000917

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00557

AC:

6191

AN:

1111986

Other (OTH)

AF:

0.00373

AC:

225

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

366

731

1097

1462

1828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00342

AC:

520

AN:

152254

Hom.:

Cov.:

AF XY:

0.00343

AC XY:

255

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41554

American (AMR)

AF:

0.00713

AC:

109

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000849

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00522

AC:

355

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00434

Hom.:

Bravo

AF:

0.00343

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00326

AC:

396

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00491

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (14)

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.030

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.5

PhyloP100

2.8

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.38

Sift

Uncertain

0.0050

Sift4G

Benign

0.084

Polyphen

0.97

Vest4

0.73

MVP

0.80

MPC

0.79

ClinPred

0.038

GERP RS

5.8

Varity_R

0.30

gMVP

0.53

Mutation Taster

=66/34

disease causing (ClinVar)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over