Genetic Variant ORMDL3:c.-22-387T>A (chr17-39924612-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.226

Publications

72 publications found

Variant links:

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]

ORMDL3 links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL3	NM_139280.4 link	c.-22-387T>A		intron_variant	Intron 1 of 3	ENST00000304046.7	NP_644809.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ORMDL3	ENST00000304046.7 link	c.-22-387T>A	intron_variant	Intron 1 of 3	1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5 link	c.-17-392T>A	intron_variant	Intron 1 of 3	1		ENSP00000464693.1
ORMDL3	ENST00000394169.5 link	c.-23+143T>A	intron_variant	Intron 3 of 5	2		ENSP00000377724.1
ORMDL3	ENST00000584000.1 link	c.-22-387T>A	intron_variant	Intron 1 of 3	4		ENSP00000464298.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

33924

Hom.:

AF XY:

0.00

AC XY:

AN XY:

18208

African (AFR)

AF:

0.00

AC:

AN:

1200

American (AMR)

AF:

0.00

AC:

AN:

3000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

856

East Asian (EAS)

AF:

0.00

AC:

AN:

1506

South Asian (SAS)

AF:

0.00

AC:

AN:

3990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

20496

Other (OTH)

AF:

0.00

AC:

AN:

1808

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.4

(source)

DANN

Benign

0.77

PhyloP100

0.23

PromoterAI

-0.0054

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over