Genetic Variant NM_016467.5:c.326+376T>G (chr2-189775189-A-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_016467.5(ORMDL1):c.326+376T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 156,426 control chromosomes in the GnomAD database, including 4,170 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 0.23 ( 4108 hom., cov: 32)

Exomes 𝑓: 0.17 ( 62 hom. )

Consequence

ORMDL1
NM_016467.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.387

Publications

17 publications found

Variant links:

Genes affected

ORMDL1 (HGNC:16036): (ORMDL sphingolipid biosynthesis regulator 1) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ORMDL1 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=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL1	NM_016467.5 link	c.326+376T>G		intron_variant	Intron 4 of 4	ENST00000392349.9	NP_057551.1	Q9P0S3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORMDL1	ENST00000392349.9 link	c.326+376T>G		intron_variant	Intron 4 of 4	1	NM_016467.5	ENSP00000376160.4		Q9P0S3

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34461

AN:

151972

Hom.:

4100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.285

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.213

Gnomad EAS

AF:

0.226

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.215

GnomAD4 exome

AF:

0.170

AC:

736

AN:

4336

Hom.:

Cov.:

AF XY:

0.163

AC XY:

367

AN XY:

2250

show subpopulations

African (AFR)

AF:

0.227

AC:

AN:

128

American (AMR)

AF:

0.182

AC:

AN:

280

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

AN:

138

East Asian (EAS)

AF:

0.227

AC:

AN:

132

South Asian (SAS)

AF:

0.116

AC:

AN:

268

European-Finnish (FIN)

AF:

0.123

AC:

AN:

138

Middle Eastern (MID)

AF:

0.100

AC:

AN:

European-Non Finnish (NFE)

AF:

0.168

AC:

508

AN:

3024

Other (OTH)

AF:

0.192

AC:

AN:

208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.227

AC:

34488

AN:

152090

Hom.:

4108

Cov.:

AF XY:

0.225

AC XY:

16744

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.285

AC:

11828

AN:

41476

American (AMR)

AF:

0.250

AC:

3818

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.213

AC:

741

AN:

3472

East Asian (EAS)

AF:

0.226

AC:

1172

AN:

5176

South Asian (SAS)

AF:

0.172

AC:

827

AN:

4822

European-Finnish (FIN)

AF:

0.194

AC:

2058

AN:

10586

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.197

AC:

13386

AN:

67962

Other (OTH)

AF:

0.217

AC:

459

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1350

2699

4049

5398

6748

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.210

Hom.:

6589

Bravo

AF:

0.232

Asia WGS

AF:

0.218

AC:

760

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.2

(source)

DANN

Benign

0.62

PhyloP100

0.39

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over