dbSNP rs9900885: ORMDL3:c.-23+686T>C (chr17-39926798-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_139280.4(ORMDL3):c.-23+686T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000995 in 986,156 control chromosomes in the GnomAD database, including 6 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 0.0045 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 4 hom. )

Consequence

ORMDL3
NM_139280.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0530

Publications

1 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 -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000354 (295/833876) while in subpopulation AFR AF = 0.0168 (266/15808). AF 95% confidence interval is 0.0152. There are 4 homozygotes in GnomAdExome4. There are 132 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 686 AD gene.

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.-23+686T>C	intron	N/A	NP_644809.1
ORMDL3	NM_001320801.2		c.-1452T>C	5_prime_UTR	Exon 1 of 6	NP_001307730.1
ORMDL3	NM_001320802.2		c.-18+686T>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.-23+686T>C	intron	N/A	ENSP00000304858.2
ORMDL3	ENST00000579695.5	TSL:1	c.-18+686T>C	intron	N/A	ENSP00000464693.1
ORMDL3	ENST00000394169.5	TSL:2	c.-1452T>C	5_prime_UTR	Exon 1 of 6	ENSP00000377724.1

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

685

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.000354

AC:

295

AN:

833876

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

132

AN XY:

385310

show subpopulations

African (AFR)

AF:

0.0168

AC:

266

AN:

15808

American (AMR)

AF:

0.00101

AC:

AN:

992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5162

East Asian (EAS)

AF:

0.00

AC:

AN:

3660

South Asian (SAS)

AF:

0.00

AC:

AN:

16478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.00000525

AC:

AN:

762506

Other (OTH)

AF:

0.000878

AC:

AN:

27342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00450

AC:

686

AN:

152280

Hom.:

Cov.:

AF XY:

0.00451

AC XY:

336

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0155

AC:

643

AN:

41554

American (AMR)

AF:

0.00222

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00319

Hom.:

Bravo

AF:

0.00533

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.5

(source)

DANN

Benign

0.83

PhyloP100

-0.053

PromoterAI

0.082

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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