12-55819156-A-G

Variant names:

• chr12-55819156-A-G
• rs182538760
• NM_014182.5:c.157A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014182.5(ORMDL2):​c.157A>G​(p.Asn53Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N53H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ORMDL2 NM_014182.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 3 publications found

Genes affected

ORMDL2 (HGNC:16037): (ORMDL sphingolipid biosynthesis regulator 2) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257390 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL2	NM_014182.5	MANE Select	c.157A>G	p.Asn53Asp	missense	Exon 2 of 4	NP_054901.1	Q53FV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL2	ENST00000243045.10	TSL:1 MANE Select	c.157A>G	p.Asn53Asp	missense	Exon 2 of 4	ENSP00000243045.5	Q53FV1
	ENSG00000257390	ENST00000546837.5	TSL:2	c.972+2845T>C		intron	N/A	ENSP00000447000.1	H0YHG0
	ORMDL2	ENST00000548974.1	TSL:2	c.157A>G	p.Asn53Asp	missense	Exon 2 of 4	ENSP00000448788.1	Q53FV1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.025	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.81		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.81
MPC		0.93
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.72
gMVP		0.98
Mutation Taster		=12/88	disease causing

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

Other links and lift over

dbSNP: rs182538760; hg19: chr12-56212940;