Genetic Variant ORMDL3:c.-22-387T>C (chr17-39924612-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_139280.4(ORMDL3):c.-22-387T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 185,784 control chromosomes in the GnomAD database, including 29,175 homozygotes. 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: 𝑓 0.56 ( 24070 hom., cov: 32)

Exomes 𝑓: 0.54 ( 5105 hom. )

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ORMDL3	NM_139280.4	MANE Select	c.-22-387T>C	intron	N/A	NP_644809.1
ORMDL3	NM_001320801.2		c.-23+143T>C	intron	N/A	NP_001307730.1
ORMDL3	NM_001320802.2		c.-17-392T>C	intron	N/A	NP_001307731.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-22-387T>C	intron	N/A	ENSP00000304858.2
ORMDL3	ENST00000579695.5	TSL:1	c.-17-392T>C	intron	N/A	ENSP00000464693.1
ORMDL3	ENST00000394169.5	TSL:2	c.-23+143T>C	intron	N/A	ENSP00000377724.1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

84998

AN:

151874

Hom.:

24063

Cov.:

show subpopulations

Gnomad AFR

AF:

0.632

Gnomad AMI

AF:

0.384

Gnomad AMR

AF:

0.578

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.721

Gnomad SAS

AF:

0.572

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.565

GnomAD4 exome

AF:

0.536

AC:

18127

AN:

33792

Hom.:

5105

AF XY:

0.539

AC XY:

9772

AN XY:

18142

show subpopulations

African (AFR)

AF:

0.607

AC:

728

AN:

1200

American (AMR)

AF:

0.609

AC:

1817

AN:

2986

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

468

AN:

852

East Asian (EAS)

AF:

0.731

AC:

1098

AN:

1502

South Asian (SAS)

AF:

0.562

AC:

2235

AN:

3976

European-Finnish (FIN)

AF:

0.466

AC:

442

AN:

948

Middle Eastern (MID)

AF:

0.583

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.505

AC:

10313

AN:

20406

Other (OTH)

AF:

0.531

AC:

956

AN:

1802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

392

784

1176

1568

1960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.559

AC:

85030

AN:

151992

Hom.:

24070

Cov.:

AF XY:

0.558

AC XY:

41494

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.631

AC:

26139

AN:

41438

American (AMR)

AF:

0.578

AC:

8824

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1873

AN:

3470

East Asian (EAS)

AF:

0.721

AC:

3717

AN:

5154

South Asian (SAS)

AF:

0.573

AC:

2764

AN:

4826

European-Finnish (FIN)

AF:

0.452

AC:

4776

AN:

10572

Middle Eastern (MID)

AF:

0.571

AC:

168

AN:

294

European-Non Finnish (NFE)

AF:

0.519

AC:

35228

AN:

67940

Other (OTH)

AF:

0.565

AC:

1192

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1920

3841

5761

7682

9602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.531

Hom.:

15419

Bravo

AF:

0.579

Asia WGS

AF:

0.586

AC:

2040

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.4

(source)

DANN

Benign

0.72

PhyloP100

0.23

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over