rs201082652

Variant names:

• chr5-132370336-G-T
• rs201082652
• NM_003060.4:c.364G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-132370336-G-T
• chr5-132370336-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 PP3 PP5

The NM_003060.4(SLC22A5):​c.364G>T​(p.Asp122Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000642 in 1,612,276 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000632547: Experimental studies have shown that this missense change affects SLC22A5 function (PMID:21864509)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D122E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15 U:4
• Conservation: PhyloP100: 5.22
• Publications: 14 publications found

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]

MIR3936HG (HGNC:40538): (MIR3936 host gene)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000632547: Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 21864509).; SCV000886116: Functional characterization in HEK293 cells indicate that the variant protein shows reduced carnitine transport activity (<10 percent of wildtype) and absence of the protein at the plasma membrane, likely due to the accumulation of the variant protein in the endoplasmic reticulum and Golgi (Toh 2011).; SCV001423613: "This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3]."; SCV002556148: "At least two publications reported experimental evidence evaluating an impact on protein function, and demonstrated markedly impaired transport function for the variant protein (e.g., Toh_2011, Koleske_2022)." PMID:32778825, 36109795, 31980526, 37510298, 36343260, 20574985, 34802252, 35281663, 32371413, 30626930, 21864509, 20208395; SCV006323408: Relevant functional assessments of this variant are available in the literature (PMID: 21864509, 36343260).; SCV005413698: PS3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• PP5: Variant 5-132370336-G-T is Pathogenic according to our data. Variant chr5-132370336-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25371.

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.364G>T	p.Asp122Tyr	missense	Exon 1 of 10	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.364G>T	p.Asp122Tyr	missense	Exon 1 of 11	NP_001295051.1	O76082-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.364G>T	p.Asp122Tyr	missense	Exon 1 of 10	ENSP00000245407.3	O76082-1
	SLC22A5	ENST00000435065.7	TSL:1	c.364G>T	p.Asp122Tyr	missense	Exon 1 of 11	ENSP00000402760.2	O76082-3
	SLC22A5	ENST00000448810.6	TSL:1	n.364G>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2	H7C1R8

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000379 AC: 91 AN: 240408 AF XY: 0.000442

Gnomad AFR exome AF: 0.0000675

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000667 AC: 974 AN: 1459912 Hom.: 1 Cov.: 34 AF XY: 0.000683 AC XY: 496 AN XY: 726144

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000442 AC: 38 AN: 86022

European-Finnish (FIN) AF: 0.0000575 AC: 3 AN: 52202

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000796 AC: 885 AN: 1111678

Other (OTH) AF: 0.000547 AC: 33 AN: 60336

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74510

African (AFR) AF: 0.000144 AC: 6 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000654

EpiControl AF: 0.000654

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
11	2	-	Renal carnitine transport defect (13)
3	1	-	not provided (4)
1	-	-	Abnormality of the nervous system (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.98
MPC		0.87
ClinPred		0.41	T
GERP RS		5.5
PromoterAI		-0.026	Neutral
Varity_R		0.61
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201082652; hg19: chr5-131706028;