17-39924612-A-T

Variant names:

• chr17-39924612-A-T
• rs4065275
• NM_139280.4:c.-22-387T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139280.4(ORMDL3):​c.-22-387T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226
• Publications: 72 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.-22-387T>A		intron	N/A	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320801.2		c.-23+143T>A		intron	N/A	NP_001307730.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.-17-392T>A		intron	N/A	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.-22-387T>A		intron	N/A	ENSP00000304858.2	Q8N138-1
	ORMDL3	ENST00000579695.5	TSL:1	c.-17-392T>A		intron	N/A	ENSP00000464693.1	Q8N138-1
	ORMDL3	ENST00000934568.1		c.-17-392T>A		intron	N/A	ENSP00000604627.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 33924 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18208

African (AFR) AF: 0.00 AC: 0 AN: 1200

American (AMR) AF: 0.00 AC: 0 AN: 3000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 856

East Asian (EAS) AF: 0.00 AC: 0 AN: 1506

South Asian (SAS) AF: 0.00 AC: 0 AN: 3990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20496

Other (OTH) AF: 0.00 AC: 0 AN: 1808

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.77
PhyloP100		0.23
PromoterAI		-0.0054	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4065275; hg19: chr17-38080865;