rs199689597

Variant names:

• chr5-132370103-C-A
• rs199689597
• NM_003060.4:c.131C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-132370103-C-A
• chr5-132370103-C-G
• chr5-132370103-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001308122.2(SLC22A5):​c.131C>A​(p.Ala44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC22A5 NM_001308122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51
• Publications: 5 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 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_001308122.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132370103-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 573546.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.131C>A	p.Ala44Glu	missense	Exon 1 of 10	NP_003051.1
	SLC22A5	NM_001308122.2		c.131C>A	p.Ala44Glu	missense	Exon 1 of 11	NP_001295051.1
	MIR3936HG	NR_110997.1		n.-187G>T		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.131C>A	p.Ala44Glu	missense	Exon 1 of 10	ENSP00000245407.3
	SLC22A5	ENST00000435065.7	TSL:1	c.131C>A	p.Ala44Glu	missense	Exon 1 of 11	ENSP00000402760.2
	SLC22A5	ENST00000448810.6	TSL:1	n.131C>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245048 AF XY: 0.00000749

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459836 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726252

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111440

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal carnitine transport defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.72
DANN	Benign	0.85
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-1.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.52
Sift	Benign	0.092	T
Sift4G	Benign	0.33	T
Polyphen		0.075	B
Vest4		0.23
MutPred		0.85		Loss of helix (P = 0.1299)
MVP		0.80
MPC		0.29
ClinPred		0.15	T
GERP RS		-6.0
PromoterAI		0.0052	Neutral
Varity_R		0.093
gMVP		0.90
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs199689597; hg19: chr5-131705795;