Genetic Variant NM_139280.4:c.*1391C>T (chr17-39921159-G-A) – 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.*1391C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 152,922 control chromosomes in the GnomAD database, including 75 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 0.027 ( 74 hom., cov: 33)

Exomes 𝑓: 0.041 ( 1 hom. )

Consequence

ORMDL3
NM_139280.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.138

Publications

10 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=-0.6).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0272 (4136/152288) while in subpopulation NFE AF = 0.0416 (2828/68018). AF 95% confidence interval is 0.0403. There are 74 homozygotes in GnomAd4. There are 1952 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL3	NM_139280.4 link	c.*1391C>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000304046.7	NP_644809.1	Q8N138-1A0A024R1W6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ORMDL3	ENST00000304046.7 link	c.*1391C>T	3_prime_UTR_variant	Exon 4 of 4	1	NM_139280.4	ENSP00000304858.2	Q8N138-1
ORMDL3	ENST00000579695.5 link	c.*1391C>T	3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000464693.1	Q8N138-1
ORMDL3	ENST00000579287.1 link	n.233C>T	non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4137

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00763

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0408

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0416

Gnomad OTH

AF:

0.0272

GnomAD4 exome

AF:

0.0410

AC:

AN:

634

Hom.:

Cov.:

AF XY:

0.0408

AC XY:

AN XY:

392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.0294

AC:

AN:

102

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0415

AC:

AN:

434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0625

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0272

AC:

4136

AN:

152288

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

1952

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00760

AC:

316

AN:

41560

American (AMR)

AF:

0.0217

AC:

332

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0210

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.0170

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0408

AC:

433

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0416

AC:

2828

AN:

68018

Other (OTH)

AF:

0.0270

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

207

413

620

826

1033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0359

Hom.:

Bravo

AF:

0.0243

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism

(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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NM_139280.4:c.*1391C>T

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