rs4646298

Variant names:

• chr5-132369527-C-T
• rs4646298
• ENST00000621103.4:n.73+317G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000457998.2(MIR3936HG):​n.122G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 162,174 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.076 (569 hom., cov: 32)
  • Exomes 𝑓: 0.079 (47 hom.)
• Consequence: MIR3936HG ENST00000457998.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.94
• Publications: 6 publications found

Genes affected

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

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, ClinGen
• short QT syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-132369527-C-T is Benign according to our data. Variant chr5-132369527-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000457998.2. 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
	MIR3936HG	NR_110997.1		n.73+317G>A		intron	N/A
	SLC22A5	NM_003060.4	MANE Select	c.-446C>T		upstream_gene	N/A	NP_003051.1	O76082-1
	SLC22A5	NM_001308122.2		c.-446C>T		upstream_gene	N/A	NP_001295051.1	O76082-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIR3936HG	ENST00000621103.4	TSL:1	n.73+317G>A		intron	N/A
	MIR3936HG	ENST00000457998.2	TSL:2	n.122G>A		non_coding_transcript_exon	Exon 1 of 2
	MIR3936HG	ENST00000649993.1		n.133G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11621 AN: 152038 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.0733

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.0762

GnomAD4 exome AF: 0.0792 AC: 793 AN: 10018 Hom.: 47 Cov.: 0 AF XY: 0.0771 AC XY: 399 AN XY: 5178

African (AFR) AF: 0.0698 AC: 30 AN: 430

American (AMR) AF: 0.0459 AC: 10 AN: 218

Ashkenazi Jewish (ASJ) AF: 0.0820 AC: 30 AN: 366

East Asian (EAS) AF: 0.278 AC: 125 AN: 450

South Asian (SAS) AF: 0.0612 AC: 6 AN: 98

European-Finnish (FIN) AF: 0.0597 AC: 45 AN: 754

Middle Eastern (MID) AF: 0.0577 AC: 3 AN: 52

European-Non Finnish (NFE) AF: 0.0684 AC: 481 AN: 7032

Other (OTH) AF: 0.102 AC: 63 AN: 618

GnomAD4 genome AF: 0.0764 AC: 11621 AN: 152156 Hom.: 569 Cov.: 32 AF XY: 0.0755 AC XY: 5617 AN XY: 74390

African (AFR) AF: 0.0616 AC: 2560 AN: 41552

American (AMR) AF: 0.0491 AC: 751 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3468

East Asian (EAS) AF: 0.267 AC: 1371 AN: 5136

South Asian (SAS) AF: 0.0650 AC: 313 AN: 4816

European-Finnish (FIN) AF: 0.0733 AC: 776 AN: 10582

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0764 AC: 5194 AN: 67992

Other (OTH) AF: 0.0764 AC: 161 AN: 2108

Alfa AF: 0.0762 Hom.: 66

Bravo AF: 0.0745

Asia WGS AF: 0.123 AC: 429 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.19
DANN	Benign	0.89
PhyloP100		-2.9
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Other links and lift over

dbSNP: rs4646298; hg19: chr5-131705219;