dbSNP rs12603332: ORMDL3:c.-23+930A>G (chr17-39926554-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001320801.2(ORMDL3):c.-1208A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 155,016 control chromosomes in the GnomAD database, including 19,086 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 0.49 ( 18730 hom., cov: 32)

Exomes 𝑓: 0.49 ( 356 hom. )

Consequence

ORMDL3
NM_001320801.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.826

Publications

77 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:

LOC124903999 (HGNC:):

LOC124903999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320801.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ORMDL3	NM_139280.4	MANE Select	c.-23+930A>G	intron	N/A	NP_644809.1	Q8N138-1
ORMDL3	NM_001320801.2		c.-1208A>G	5_prime_UTR	Exon 1 of 6	NP_001307730.1	Q8N138-1
ORMDL3	NM_001320802.2		c.-18+930A>G	intron	N/A	NP_001307731.1	Q8N138-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-23+930A>G	intron	N/A	ENSP00000304858.2	Q8N138-1
ORMDL3	ENST00000579695.5	TSL:1	c.-18+930A>G	intron	N/A	ENSP00000464693.1	Q8N138-1
ORMDL3	ENST00000394169.5	TSL:2	c.-1208A>G	5_prime_UTR	Exon 1 of 6	ENSP00000377724.1	Q8N138-1

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74583

AN:

151934

Hom.:

18737

Cov.:

show subpopulations

Gnomad AFR

AF:

0.392

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.542

Gnomad EAS

AF:

0.722

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.451

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.517

Gnomad OTH

AF:

0.518

GnomAD4 exome

AF:

0.485

AC:

1439

AN:

2964

Hom.:

356

Cov.:

AF XY:

0.492

AC XY:

728

AN XY:

1480

show subpopulations

African (AFR)

AF:

0.328

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.563

AC:

AN:

East Asian (EAS)

AF:

0.875

AC:

AN:

South Asian (SAS)

AF:

0.579

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.667

AC:

AN:

European-Non Finnish (NFE)

AF:

0.484

AC:

1319

AN:

2724

Other (OTH)

AF:

0.518

AC:

AN:

112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.490

AC:

74578

AN:

152052

Hom.:

18730

Cov.:

AF XY:

0.490

AC XY:

36432

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.392

AC:

16240

AN:

41474

American (AMR)

AF:

0.554

AC:

8469

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

1878

AN:

3466

East Asian (EAS)

AF:

0.722

AC:

3726

AN:

5160

South Asian (SAS)

AF:

0.571

AC:

2754

AN:

4826

European-Finnish (FIN)

AF:

0.451

AC:

4754

AN:

10550

Middle Eastern (MID)

AF:

0.551

AC:

162

AN:

294

European-Non Finnish (NFE)

AF:

0.517

AC:

35153

AN:

67978

Other (OTH)

AF:

0.519

AC:

1091

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1924

3847

5771

7694

9618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.504

Hom.:

34838

Bravo

AF:

0.500

Asia WGS

AF:

0.572

AC:

1991

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.83

PromoterAI

0.21

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