NM_003060.4:c.1249A>G

Variant names:

• chr5-132390886-A-G
• rs139775414
• NM_003060.4:c.1249A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003060.4(SLC22A5):​c.1249A>G​(p.Met417Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,613,996 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M417I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: SLC22A5 NM_003060.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.928
• 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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067510307).
• BP6: Variant 5-132390886-A-G is Benign according to our data. Variant chr5-132390886-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 460395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00338 (515/152244) while in subpopulation AFR AF = 0.0118 (488/41524). AF 95% confidence interval is 0.0109. There are 2 homozygotes in GnomAd4. There are 242 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1249A>G	p.Met417Val	missense	Exon 7 of 10	NP_003051.1
	SLC22A5	NM_001308122.2		c.1321A>G	p.Met441Val	missense	Exon 8 of 11	NP_001295051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A5	ENST00000245407.8	TSL:1 MANE Select	c.1249A>G	p.Met417Val	missense	Exon 7 of 10	ENSP00000245407.3
	SLC22A5	ENST00000435065.7	TSL:1	c.1321A>G	p.Met441Val	missense	Exon 8 of 11	ENSP00000402760.2
	SLC22A5	ENST00000448810.6	TSL:1	n.*101A>G		non_coding_transcript_exon	Exon 7 of 10	ENSP00000401860.2

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152126 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000994 AC: 250 AN: 251406 AF XY: 0.000640

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000391 AC: 571 AN: 1461752 Hom.: 4 Cov.: 30 AF XY: 0.000326 AC XY: 237 AN XY: 727174

African (AFR) AF: 0.0123 AC: 411 AN: 33474

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5740

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111936

Other (OTH) AF: 0.000861 AC: 52 AN: 60382

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152244 Hom.: 2 Cov.: 33 AF XY: 0.00325 AC XY: 242 AN XY: 74448

African (AFR) AF: 0.0118 AC: 488 AN: 41524

American (AMR) AF: 0.00111 AC: 17 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00164 Hom.: 5

Bravo AF: 0.00413

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Renal carnitine transport defect (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N
PhyloP100		0.93
PrimateAI	Benign	0.38	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.069
Sift	Benign	0.39	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.67
MPC		0.21
ClinPred		0.0011	T
GERP RS		1.9
Varity_R		0.047
gMVP		0.28
Mutation Taster		=98/2	polymorphism

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: rs139775414; hg19: chr5-131726578; COSMIC: COSV99810247; COSMIC: COSV99810247;