NM_003060.4:c.272A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_003060.4(SLC22A5):c.272A>G(p.Asn91Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000565 in 1,576,526 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N91T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8

Conservation

PhyloP100: 5.67

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_003060.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132370244-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2913829.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.14530244).

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.272A>G	p.Asn91Ser	missense	Exon 1 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.272A>G	p.Asn91Ser	missense	Exon 1 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.272A>G	p.Asn91Ser	missense	Exon 1 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.272A>G	p.Asn91Ser	missense	Exon 1 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.272A>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.00143

GnomAD2 exomes

AF:

0.0000390

AC:

AN:

179466

AF XY:

0.0000204

show subpopulations

Gnomad AFR exome

AF:

0.000334

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000207

GnomAD4 exome

AF:

0.0000232

AC:

AN:

1424258

Hom.:

Cov.:

AF XY:

0.0000184

AC XY:

AN XY:

705306

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

32438

American (AMR)

AF:

0.000393

AC:

AN:

38160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25590

East Asian (EAS)

AF:

0.00

AC:

AN:

37172

South Asian (SAS)

AF:

0.00

AC:

AN:

82134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1094898

Other (OTH)

AF:

0.000152

AC:

AN:

59106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000368

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41566

American (AMR)

AF:

0.00209

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000584

Hom.:

Bravo

AF:

0.000672

ExAC

AF:

0.0000255

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (5)

not provided (2)

Decreased circulating carnitine concentration (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.034

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.1

PhyloP100

5.7

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.38

Sift

Benign

0.082

Sift4G

Benign

0.12

Polyphen

0.94

Vest4

0.29

MVP

0.86

MPC

0.18

ClinPred

0.29

GERP RS

5.5

PromoterAI

-0.0054

Neutral

(source)

Varity_R

0.28

gMVP

0.79

Mutation Taster

=19/81

disease causing

(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