NM_016467.5:c.118A>G

Variant names:

• chr2-189782478-T-C
• NM_016467.5:c.118A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016467.5(ORMDL1):​c.118A>G​(p.Ile40Val) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ORMDL1 NM_016467.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.94
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37600273).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016467.5. 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
	ORMDL1	NM_016467.5	MANE Select	c.118A>G	p.Ile40Val	missense	Exon 3 of 5	NP_057551.1	Q9P0S3
	ORMDL1	NM_001371385.1		c.118A>G	p.Ile40Val	missense	Exon 2 of 5	NP_001358314.1	A0ABB0MVM0
	ORMDL1	NM_001371386.1		c.118A>G	p.Ile40Val	missense	Exon 3 of 6	NP_001358315.1	A0ABB0MVM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL1	ENST00000392349.9	TSL:1 MANE Select	c.118A>G	p.Ile40Val	missense	Exon 3 of 5	ENSP00000376160.4	Q9P0S3
	ORMDL1	ENST00000325795.7	TSL:1	c.118A>G	p.Ile40Val	missense	Exon 1 of 3	ENSP00000326869.3	Q9P0S3
	ORMDL1	ENST00000392350.7	TSL:1	c.118A>G	p.Ile40Val	missense	Exon 2 of 4	ENSP00000376161.3	Q9P0S3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	0.0037	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.99	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.14
Sift	Benign	0.50	T
Sift4G	Benign	0.38	T
Polyphen		0.0030	B
Vest4		0.61
MutPred		0.47		Gain of catalytic residue at I40 (P = 0.1072)
MVP		0.35
MPC		0.33
ClinPred		0.78	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.86
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

hg19: chr2-190647204;