Genetic Variant NM_003060.4:c.394-1945A>G (chr5-132376433-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003060.4(SLC22A5):c.394-1945A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 152,000 control chromosomes in the GnomAD database, including 6,937 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 6934 hom., cov: 31)

Exomes 𝑓: 0.21 ( 3 hom. )

Consequence

SLC22A5
NM_003060.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.74

Publications

14 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: Ambry Genetics, ClinGen, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4 link	c.394-1945A>G		intron_variant	Intron 1 of 9	ENST00000245407.8	NP_003051.1	O76082-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8 link	c.394-1945A>G		intron_variant	Intron 1 of 9	1	NM_003060.4	ENSP00000245407.3		O76082-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43435

AN:

151776

Hom.:

6933

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.130

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.426

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.286

GnomAD4 exome

AF:

0.208

AC:

AN:

106

Hom.:

Cov.:

AF XY:

0.218

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.167

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.195

AC:

AN:

Other (OTH)

AF:

0.300

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.286

AC:

43446

AN:

151894

Hom.:

6934

Cov.:

AF XY:

0.298

AC XY:

22122

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.167

AC:

6929

AN:

41454

American (AMR)

AF:

0.289

AC:

4405

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1038

AN:

3468

East Asian (EAS)

AF:

0.376

AC:

1941

AN:

5158

South Asian (SAS)

AF:

0.560

AC:

2678

AN:

4784

European-Finnish (FIN)

AF:

0.426

AC:

4499

AN:

10550

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21118

AN:

67920

Other (OTH)

AF:

0.287

AC:

603

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1457

2914

4370

5827

7284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.298

Hom.:

11959

Bravo

AF:

0.263

Asia WGS

AF:

0.463

AC:

1608

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.0020

(source)

DANN

Benign

0.71

PhyloP100

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over