chr17-39924659-G-C

Variant names:

• chr17-39924659-G-C
• rs8076131
• NM_139280.4:c.-22-434C>G

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.-22-434C>G 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: -3.60
• Publications: 89 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=-0.84).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	NM_139280.4	MANE Select	c.-22-434C>G		intron	N/A	NP_644809.1
	ORMDL3	NM_001320801.2		c.-23+96C>G		intron	N/A	NP_001307730.1
	ORMDL3	NM_001320802.2		c.-17-439C>G		intron	N/A	NP_001307731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-22-434C>G		intron	N/A	ENSP00000304858.2
	ORMDL3	ENST00000579695.5	TSL:1	c.-17-439C>G		intron	N/A	ENSP00000464693.1
	ORMDL3	ENST00000394169.5	TSL:2	c.-23+96C>G		intron	N/A	ENSP00000377724.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 5002 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2724

African (AFR) AF: 0.00 AC: 0 AN: 132

American (AMR) AF: 0.00 AC: 0 AN: 898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 100

East Asian (EAS) AF: 0.00 AC: 0 AN: 132

South Asian (SAS) AF: 0.00 AC: 0 AN: 420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 98

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2976

Other (OTH) AF: 0.00 AC: 0 AN: 236

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 6645

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.15
DANN	Benign	0.44
PhyloP100		-3.6
PromoterAI		-0.035	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: rs8076131; hg19: chr17-38080912;