rs8076131

Positions:

• chr17-39924659-G-A
• chr17-39924659-G-C

Variant summary

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

The NM_139280.4(ORMDL3):​c.-22-434C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 157,060 control chromosomes in the GnomAD database, including 32,448 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 0.63 (31619 hom., cov: 32)
  • Exomes 𝑓: 0.56 (829 hom.)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.60

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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORMDL3	NM_139280.4	c.-22-434C>T		intron_variant		ENST00000304046.7	NP_644809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORMDL3	ENST00000304046.7	c.-22-434C>T		intron_variant		1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5	c.-17-439C>T		intron_variant		1		ENSP00000464693.1
ORMDL3	ENST00000394169.5	c.-23+96C>T		intron_variant		2		ENSP00000377724.1
ORMDL3	ENST00000584000.1	c.-22-434C>T		intron_variant		4		ENSP00000464298.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96066 AN: 151954 Hom.: 31582 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.631

GnomAD4 exome AF: 0.560 AC: 2793 AN: 4988 Hom.: 829 AF XY: 0.567 AC XY: 1543 AN XY: 2720

Gnomad4 AFR exome AF: 0.833

Gnomad4 AMR exome AF: 0.651

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.689

Gnomad4 SAS exome AF: 0.603

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.627

GnomAD4 genome AF: 0.632 AC: 96150 AN: 152072 Hom.: 31619 Cov.: 32 AF XY: 0.629 AC XY: 46740 AN XY: 74342

Gnomad4 AFR AF: 0.820

Gnomad4 AMR AF: 0.615

Gnomad4 ASJ AF: 0.592

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.478

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.633

Alfa AF: 0.613 Hom.: 5468

Bravo AF: 0.658

Asia WGS AF: 0.626 AC: 2177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.18
DANN	Benign	0.24

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: rs8076131; hg19: chr17-38080912;