17-39922663-T-C

Variant names:

• chr17-39922663-T-C
• rs1978305333
• NM_139280.4:c.349A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139280.4(ORMDL3):​c.349A>G​(p.Thr117Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,636 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T117P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

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.349A>G	p.Thr117Ala	missense	Exon 4 of 4	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320801.2		c.349A>G	p.Thr117Ala	missense	Exon 6 of 6	NP_001307730.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.349A>G	p.Thr117Ala	missense	Exon 4 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.349A>G	p.Thr117Ala	missense	Exon 4 of 4	ENSP00000304858.2	Q8N138-1
	ORMDL3	ENST00000579695.5	TSL:1	c.349A>G	p.Thr117Ala	missense	Exon 4 of 4	ENSP00000464693.1	Q8N138-1
	ORMDL3	ENST00000584220.5	TSL:1	c.301A>G	p.Thr101Ala	missense	Exon 3 of 3	ENSP00000464455.1	Q8N138-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461636 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.82	P
Vest4		0.84
MutPred		0.69		Loss of stability (P = 0.0613)
MVP		0.41
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.54
gMVP		0.98
Mutation Taster		=65/35	polymorphism

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: rs1978305333; hg19: chr17-38078916;