2-189782423-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016467.5(ORMDL1):​c.173T>C​(p.Leu58Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ORMDL1
NM_016467.5 missense, splice_region

Scores

5
5
9
Splicing: ADA: 0.02148
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.23
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ORMDL1NM_016467.5 linkc.173T>C p.Leu58Pro missense_variant, splice_region_variant Exon 3 of 5 ENST00000392349.9 NP_057551.1 Q9P0S3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ORMDL1ENST00000392349.9 linkc.173T>C p.Leu58Pro missense_variant, splice_region_variant Exon 3 of 5 1 NM_016467.5 ENSP00000376160.4 Q9P0S3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
33
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248994
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457270
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
724480
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152332
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 13, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.173T>C (p.L58P) alteration is located in exon 3 (coding exon 1) of the ORMDL1 gene. This alteration results from a T to C substitution at nucleotide position 173, causing the leucine (L) at amino acid position 58 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.25
T;T;T;T;T;T
Eigen
Benign
0.10
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.54
.;.;T;T;.;T
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.63
D;D;D;D;D;D
MetaSVM
Benign
-0.53
T
MutationAssessor
Uncertain
2.4
M;M;M;.;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.4
D;D;D;D;D;D
REVEL
Uncertain
0.34
Sift
Benign
0.060
T;T;T;T;T;T
Sift4G
Benign
0.15
T;T;T;T;.;.
Polyphen
0.0
B;B;B;.;.;.
Vest4
0.92
MutPred
0.55
Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP
0.78
MPC
0.60
ClinPred
0.96
D
GERP RS
4.7
Varity_R
0.85
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.021
dbscSNV1_RF
Benign
0.14
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs527773099; hg19: chr2-190647149; API