rs756863825

Variant names:

• chr5-132370012-T-A
• rs756863825
• NM_003060.4:c.40T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_003060.4(SLC22A5):​c.40T>A​(p.Trp14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,916 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W14C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 2.83
• Publications: 1 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 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_003060.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132370014-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1439444.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• PP5: Variant 5-132370012-T-A is Pathogenic according to our data. Variant chr5-132370012-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 580421.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	NM_003060.4	MANE Select	c.40T>A	p.Trp14Arg	missense	Exon 1 of 10	NP_003051.1
	SLC22A5	NM_001308122.2		c.40T>A	p.Trp14Arg	missense	Exon 1 of 11	NP_001295051.1
	MIR3936HG	NR_110997.1		n.-96A>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.40T>A	p.Trp14Arg	missense	Exon 1 of 10	ENSP00000245407.3
	SLC22A5	ENST00000435065.7	TSL:1	c.40T>A	p.Trp14Arg	missense	Exon 1 of 11	ENSP00000402760.2
	SLC22A5	ENST00000448810.6	TSL:1	n.40T>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460916 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111692

Other (OTH) AF: 0.0000331 AC: 2 AN: 60354

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Renal carnitine transport defect (2)
-	1	-	Decreased circulating carnitine concentration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.75		Gain of methylation at W14 (P = 0.0165)
MVP		0.98
MPC		0.74
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.0046	Neutral
Varity_R		0.94
gMVP		0.97
Mutation Taster		=15/85	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: rs756863825; hg19: chr5-131705704;