17-39924179-C-A

Variant names:

• chr17-39924179-C-A
• rs765427187
• NM_139280.4:c.25G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_139280.4(ORMDL3):​c.25G>T​(p.Glu9*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139280.4. 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
	ORMDL3	NM_139280.4	MANE Select	c.25G>T	p.Glu9*	stop_gained	Exon 2 of 4	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320801.2		c.25G>T	p.Glu9*	stop_gained	Exon 4 of 6	NP_001307730.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.25G>T	p.Glu9*	stop_gained	Exon 2 of 4	NP_001307731.1	Q8N138-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.25G>T	p.Glu9*	stop_gained	Exon 2 of 4	ENSP00000304858.2	Q8N138-1
	ORMDL3	ENST00000579695.5	TSL:1	c.25G>T	p.Glu9*	stop_gained	Exon 2 of 4	ENSP00000464693.1	Q8N138-1
	ORMDL3	ENST00000584220.5	TSL:1	c.25G>T	p.Glu9*	stop_gained	Exon 1 of 3	ENSP00000464455.1	Q8N138-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457374 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 85438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109576

Other (OTH) AF: 0.00 AC: 0 AN: 60220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.9
Vest4		0.86
GERP RS		6.0
PromoterAI		-0.0011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs765427187; hg19: chr17-38080432;