rs4065275

Positions:

• chr17-39924612-A-G
• chr17-39924612-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139280.4(ORMDL3):​c.-22-387T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 185,784 control chromosomes in the GnomAD database, including 29,175 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (24070 hom., cov: 32)
  • Exomes 𝑓: 0.54 (5105 hom.)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226

Genes affected

ORMDL3 (HGNC:16038): (ORMDL sphingolipid biosynthesis regulator 3) Involved in ceramide metabolic process. Acts upstream of or within several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of SPOTS complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORMDL3	NM_139280.4	c.-22-387T>C		intron_variant		ENST00000304046.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORMDL3	ENST00000304046.7	c.-22-387T>C		intron_variant		1	NM_139280.4	P1
ORMDL3	ENST00000579695.5	c.-17-392T>C		intron_variant		1		P1
ORMDL3	ENST00000394169.5	c.-23+143T>C		intron_variant		2		P1
ORMDL3	ENST00000584000.1	c.-22-387T>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.560 AC: 84998 AN: 151874 Hom.: 24063 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.536 AC: 18127 AN: 33792 Hom.: 5105 AF XY: 0.539 AC XY: 9772 AN XY: 18142

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.609

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.731

Gnomad4 SAS exome AF: 0.562

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.531

GnomAD4 genome AF: 0.559 AC: 85030 AN: 151992 Hom.: 24070 Cov.: 32 AF XY: 0.558 AC XY: 41494 AN XY: 74298

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.578

Gnomad4 ASJ AF: 0.540

Gnomad4 EAS AF: 0.721

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.565

Alfa AF: 0.529 Hom.: 11179

Bravo AF: 0.579

Asia WGS AF: 0.586 AC: 2040 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs4065275; hg19: chr17-38080865;