17-39927109-G-C

Variant names:

• chr17-39927109-G-C
• rs35739333
• NM_139280.4:c.-23+375C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_139280.4(ORMDL3):​c.-23+375C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 544,498 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000092 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 1 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]

LOC124903999 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.-23+375C>G		intron	N/A	NP_644809.1
	ORMDL3	NM_001320802.2		c.-18+375C>G		intron	N/A	NP_001307731.1
	ORMDL3	NM_001320801.2		c.-1763C>G		upstream_gene	N/A	NP_001307730.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-23+375C>G		intron	N/A	ENSP00000304858.2
	ORMDL3	ENST00000579695.5	TSL:1	c.-18+375C>G		intron	N/A	ENSP00000464693.1
	ORMDL3	ENST00000584000.1	TSL:4	c.-65C>G		5_prime_UTR	Exon 1 of 4	ENSP00000464298.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000918 AC: 5 AN: 544498 Hom.: 0 Cov.: 6 AF XY: 0.0000118 AC XY: 3 AN XY: 254396

African (AFR) AF: 0.00 AC: 0 AN: 9918

American (AMR) AF: 0.00 AC: 0 AN: 624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 2226

South Asian (SAS) AF: 0.00 AC: 0 AN: 10814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1116

European-Non Finnish (NFE) AF: 0.0000100 AC: 5 AN: 498494

Other (OTH) AF: 0.00 AC: 0 AN: 17818

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.24
DANN	Benign	0.79
PhyloP100		-1.2
PromoterAI		-0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35739333; hg19: chr17-38083362;