5-132395612-A-T

Variant names:

• chr5-132395612-A-T
• rs274547
• NM_003060.4:c.*1340A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_003060.4(SLC22A5):​c.*1340A>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 152,778 control chromosomes in the GnomAD database, including 45,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (44807 hom., cov: 33)
  • Exomes 𝑓: 0.83 (198 hom.)
• Consequence: SLC22A5 NM_003060.4 splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.34
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-132395612-A-T is Benign according to our data. Variant chr5-132395612-A-T is described in ClinVar as Benign. ClinVar VariationId is 907610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A5	NM_003060.4	c.*1340A>T		splice_region_variant	Exon 10 of 10	ENST00000245407.8	NP_003051.1
SLC22A5	NM_003060.4	c.*1340A>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000245407.8	NP_003051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A5	ENST00000245407.8	c.*1340A>T		splice_region_variant	Exon 10 of 10	1	NM_003060.4	ENSP00000245407.3
SLC22A5	ENST00000245407.8	c.*1340A>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_003060.4	ENSP00000245407.3

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114408 AN: 152092 Hom.: 44809 Cov.: 33

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.789

GnomAD4 exome AF: 0.835 AC: 474 AN: 568 Hom.: 198 Cov.: 0 AF XY: 0.841 AC XY: 281 AN XY: 334

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.775 AC: 107 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.856 AC: 363 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.500 AC: 2 AN: 4

GnomAD4 genome AF: 0.752 AC: 114435 AN: 152210 Hom.: 44807 Cov.: 33 AF XY: 0.756 AC XY: 56252 AN XY: 74430

African (AFR) AF: 0.508 AC: 21071 AN: 41492

American (AMR) AF: 0.810 AC: 12393 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 3017 AN: 3472

East Asian (EAS) AF: 0.911 AC: 4721 AN: 5184

South Asian (SAS) AF: 0.831 AC: 4011 AN: 4828

European-Finnish (FIN) AF: 0.870 AC: 9212 AN: 10594

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57363 AN: 68020

Other (OTH) AF: 0.783 AC: 1655 AN: 2114

Alfa AF: 0.787 Hom.: 6072

Bravo AF: 0.738

Asia WGS AF: 0.803 AC: 2788 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal carnitine transport defect Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		3.3
Mutation Taster		=99/1	polymorphism (auto)

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: rs274547; hg19: chr5-131731304;