dbSNP rs17608925: ORMDL3:c.-23+906A>G (chr17-39926578-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001320801.2(ORMDL3):c.-1232A>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 0.098 in 166,448 control chromosomes in the GnomAD database, including 910 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 0.097 ( 827 hom., cov: 32)

Exomes 𝑓: 0.11 ( 83 hom. )

Consequence

ORMDL3
NM_001320801.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0980

Publications

19 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=-0.68).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 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+906A>G	intron	N/A	NP_644809.1	Q8N138-1
ORMDL3	NM_001320801.2		c.-1232A>G	5_prime_UTR	Exon 1 of 6	NP_001307730.1	Q8N138-1
ORMDL3	NM_001320802.2		c.-18+906A>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+906A>G	intron	N/A	ENSP00000304858.2	Q8N138-1
ORMDL3	ENST00000579695.5	TSL:1	c.-18+906A>G	intron	N/A	ENSP00000464693.1	Q8N138-1
ORMDL3	ENST00000394169.5	TSL:2	c.-1232A>G	5_prime_UTR	Exon 1 of 6	ENSP00000377724.1	Q8N138-1

Frequencies

GnomAD3 genomes

AF:

0.0970

AC:

14756

AN:

152136

Hom.:

825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0575

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0808

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0962

GnomAD4 exome

AF:

0.110

AC:

1558

AN:

14194

Hom.:

Cov.:

AF XY:

0.109

AC XY:

770

AN XY:

7042

show subpopulations

African (AFR)

AF:

0.0395

AC:

AN:

228

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0882

AC:

AN:

102

East Asian (EAS)

AF:

0.125

AC:

AN:

South Asian (SAS)

AF:

0.113

AC:

AN:

240

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.111

AC:

1450

AN:

13056

Other (OTH)

AF:

0.117

AC:

AN:

470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0969

AC:

14758

AN:

152254

Hom.:

827

Cov.:

AF XY:

0.102

AC XY:

7570

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0573

AC:

2380

AN:

41564

American (AMR)

AF:

0.114

AC:

1742

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

384

AN:

3470

East Asian (EAS)

AF:

0.0808

AC:

418

AN:

5172

South Asian (SAS)

AF:

0.156

AC:

752

AN:

4824

European-Finnish (FIN)

AF:

0.169

AC:

1789

AN:

10602

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.101

AC:

6889

AN:

68016

Other (OTH)

AF:

0.0956

AC:

202

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

687

1374

2061

2748

3435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0962

Hom.:

1161

Bravo

AF:

0.0881

Asia WGS

AF:

0.100

AC:

349

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

-0.098

PromoterAI

0.12

Neutral

(source)

Mutation Taster

=300/0

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