dbSNP rs8076131: ORMDL3:c.-22-434C>T (chr17-39924659-G-A) – 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.-22-434C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 157,060 control chromosomes in the GnomAD database, including 32,448 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 0.63 ( 31619 hom., cov: 32)

Exomes 𝑓: 0.56 ( 829 hom. )

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL3	NM_139280.4 link	c.-22-434C>T		intron_variant	Intron 1 of 3	ENST00000304046.7	NP_644809.1	Q8N138-1A0A024R1W6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ORMDL3	ENST00000304046.7 link	c.-22-434C>T	intron_variant	Intron 1 of 3	1	NM_139280.4	ENSP00000304858.2	Q8N138-1
ORMDL3	ENST00000579695.5 link	c.-17-439C>T	intron_variant	Intron 1 of 3	1		ENSP00000464693.1	Q8N138-1
ORMDL3	ENST00000394169.5 link	c.-23+96C>T	intron_variant	Intron 3 of 5	2		ENSP00000377724.1	Q8N138-1
ORMDL3	ENST00000584000.1 link	c.-22-434C>T	intron_variant	Intron 1 of 3	4		ENSP00000464298.1	J3QRM9

Frequencies

GnomAD3 genomes

AF:

0.632

AC:

96066

AN:

151954

Hom.:

31582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.820

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.616

Gnomad ASJ

AF:

0.592

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.592

Gnomad FIN

AF:

0.478

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.548

Gnomad OTH

AF:

0.631

GnomAD4 exome

AF:

0.560

AC:

2793

AN:

4988

Hom.:

829

AF XY:

0.567

AC XY:

1543

AN XY:

2720

show subpopulations

African (AFR)

AF:

0.833

AC:

110

AN:

132

American (AMR)

AF:

0.651

AC:

582

AN:

894

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

AN:

100

East Asian (EAS)

AF:

0.689

AC:

AN:

132

South Asian (SAS)

AF:

0.603

AC:

252

AN:

418

European-Finnish (FIN)

AF:

0.439

AC:

AN:

Middle Eastern (MID)

AF:

0.800

AC:

AN:

European-Non Finnish (NFE)

AF:

0.504

AC:

1497

AN:

2968

Other (OTH)

AF:

0.627

AC:

148

AN:

236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.632

AC:

96150

AN:

152072

Hom.:

31619

Cov.:

AF XY:

0.629

AC XY:

46740

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.820

AC:

34022

AN:

41484

American (AMR)

AF:

0.615

AC:

9401

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.592

AC:

2053

AN:

3468

East Asian (EAS)

AF:

0.722

AC:

3726

AN:

5164

South Asian (SAS)

AF:

0.592

AC:

2852

AN:

4820

European-Finnish (FIN)

AF:

0.478

AC:

5055

AN:

10574

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.548

AC:

37209

AN:

67956

Other (OTH)

AF:

0.633

AC:

1339

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1694

3388

5082

6776

8470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

774

1548

2322

3096

3870

<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:

0.626

Hom.:

6645

Bravo

AF:

0.658

Asia WGS

AF:

0.626

AC:

2177

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.18

(source)

DANN

Benign

0.24

PhyloP100

-3.6

PromoterAI

-0.037

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over