Genetic Variant NM_139280.4:c.-23+375C>A (chr17-39927109-G-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_139280.4(ORMDL3):c.-23+375C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 696,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ORMDL3
NM_139280.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.22

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High AC in GnomAdExome4 at 30 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+375C>A	intron	N/A	NP_644809.1
ORMDL3	NM_001320802.2		c.-18+375C>A	intron	N/A	NP_001307731.1
ORMDL3	NM_001320801.2		c.-1763C>A	upstream_gene	N/A	NP_001307730.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-23+375C>A	intron	N/A	ENSP00000304858.2
ORMDL3	ENST00000579695.5	TSL:1	c.-18+375C>A	intron	N/A	ENSP00000464693.1
ORMDL3	ENST00000584000.1	TSL:4	c.-65C>A	5_prime_UTR	Exon 1 of 4	ENSP00000464298.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000551

AC:

AN:

544498

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

254396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9918

American (AMR)

AF:

0.00

AC:

AN:

624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3314

East Asian (EAS)

AF:

0.00

AC:

AN:

2226

South Asian (SAS)

AF:

0.00

AC:

AN:

10814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1116

European-Non Finnish (NFE)

AF:

0.0000562

AC:

AN:

498494

Other (OTH)

AF:

0.000112

AC:

AN:

17818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.26

(source)

DANN

Benign

0.90

PhyloP100

-1.2

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over