Genetic Variant ORMDL3:c.-22-434C>G (chr17-39924659-G-C) – 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.-22-434C>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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.60

Publications

89 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=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL3	NM_139280.4 link	c.-22-434C>G		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.-22-434C>G	intron_variant	Intron 1 of 3	1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5 link	c.-17-439C>G	intron_variant	Intron 1 of 3	1		ENSP00000464693.1
ORMDL3	ENST00000394169.5 link	c.-23+96C>G	intron_variant	Intron 3 of 5	2		ENSP00000377724.1
ORMDL3	ENST00000584000.1 link	c.-22-434C>G	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:

5002

Hom.:

AF XY:

0.00

AC XY:

AN XY:

2724

African (AFR)

AF:

0.00

AC:

AN:

132

American (AMR)

AF:

0.00

AC:

AN:

898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

100

East Asian (EAS)

AF:

0.00

AC:

AN:

132

South Asian (SAS)

AF:

0.00

AC:

AN:

420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

2976

Other (OTH)

AF:

0.00

AC:

AN:

236

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

6645

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.15

(source)

DANN

Benign

0.44

PhyloP100

-3.6

PromoterAI

-0.035

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