Genetic Variant NM_003060.4:c.59T>A (chr5-132370031-T-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_003060.4(SLC22A5):c.59T>A(p.Leu20His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,613,396 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 4 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.30

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.010430038).

BP6

Variant 5-132370031-T-A is Benign according to our data. Variant chr5-132370031-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25352.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00335 (510/152274) while in subpopulation AFR AF = 0.0117 (485/41560). AF 95% confidence interval is 0.0108. There are 4 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	NM_003060.4	MANE Select	c.59T>A	p.Leu20His	missense	Exon 1 of 10	NP_003051.1	O76082-1
SLC22A5	NM_001308122.2		c.59T>A	p.Leu20His	missense	Exon 1 of 11	NP_001295051.1	O76082-3
MIR3936HG	NR_110997.1		n.-115A>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.59T>A	p.Leu20His	missense	Exon 1 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.59T>A	p.Leu20His	missense	Exon 1 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.59T>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.00335

AC:

509

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00101

AC:

253

AN:

249310

AF XY:

0.000658

show subpopulations

Gnomad AFR exome

AF:

0.0128

Gnomad AMR exome

AF:

0.000899

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000382

AC:

558

AN:

1461122

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

235

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.0119

AC:

399

AN:

33458

American (AMR)

AF:

0.000962

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:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111728

Other (OTH)

AF:

0.000861

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00335

AC:

510

AN:

152274

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0117

AC:

485

AN:

41560

American (AMR)

AF:

0.00111

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68004

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

114

142

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:

0.000982

Hom.:

Bravo

AF:

0.00411

ESP6500AA

AF:

0.0148

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00132

AC:

160

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.81

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

3.2

PhyloP100

2.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.49

Sift

Benign

0.11

Sift4G

Benign

0.22

Polyphen

0.97

Vest4

0.60

MVP

0.97

MPC

0.31

ClinPred

0.054

GERP RS

5.2

PromoterAI

0.021

Neutral

(source)

Varity_R

0.35

gMVP

0.84

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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