Genetic Variant NM_003060.4:c.1345T>G (chr5-132392510-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1PM5PP3PP5BP4BS1_Supporting

The NM_003060.4(SLC22A5):c.1345T>G(p.Tyr449Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,614,180 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. Y449C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SLC22A5
NM_003060.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:6

Conservation

PhyloP100: 4.74

Publications

19 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_003060.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132392511-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1310598.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 5-132392510-T-G is Pathogenic according to our data. Variant chr5-132392510-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25420.

BP4

Computational evidence support a benign effect (MetaRNN=0.104227066). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00108 (165/152336) while in subpopulation AFR AF = 0.00373 (155/41574). AF 95% confidence interval is 0.00325. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1345T>G	p.Tyr449Asp	missense	Exon 8 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.1417T>G	p.Tyr473Asp	missense	Exon 9 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.1345T>G	p.Tyr449Asp	missense	Exon 8 of 10	ENSP00000245407.3	O76082-1
SLC22A5	ENST00000435065.7	TSL:1	c.1417T>G	p.Tyr473Asp	missense	Exon 9 of 11	ENSP00000402760.2	O76082-3
SLC22A5	ENST00000448810.6	TSL:1	n.*197T>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000254

AC:

AN:

251478

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.0000289

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:

0.000163

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00430

AC:

144

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111966

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00108

AC:

165

AN:

152336

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00373

AC:

155

AN:

41574

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000452

Hom.:

Bravo

AF:

0.00122

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Renal carnitine transport defect (6)

not provided (5)

Acute rhabdomyolysis (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.10

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

PhyloP100

4.7

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.91

MVP

1.0

MPC

1.1

ClinPred

0.34

GERP RS

6.2

Varity_R

0.97

gMVP

0.92

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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