chr2-189775581-T-C

Variant names:

• chr2-189775581-T-C
• rs986598114
• NM_016467.5:c.310A>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.310A>G​(p.Ile104Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,600,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• 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=0.3485787).

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.310A>G	p.Ile104Val	missense	Exon 4 of 5	NP_057551.1	Q9P0S3
	ORMDL1	NM_001371385.1		c.310A>G	p.Ile104Val	missense	Exon 3 of 5	NP_001358314.1	A0ABB0MVM0
	ORMDL1	NM_001371386.1		c.310A>G	p.Ile104Val	missense	Exon 4 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.310A>G	p.Ile104Val	missense	Exon 4 of 5	ENSP00000376160.4	Q9P0S3
	ORMDL1	ENST00000325795.7	TSL:1	c.310A>G	p.Ile104Val	missense	Exon 2 of 3	ENSP00000326869.3	Q9P0S3
	ORMDL1	ENST00000392350.7	TSL:1	c.310A>G	p.Ile104Val	missense	Exon 3 of 4	ENSP00000376161.3	Q9P0S3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448586 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 720254

African (AFR) AF: 0.00 AC: 0 AN: 32662

American (AMR) AF: 0.0000235 AC: 1 AN: 42628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 38986

South Asian (SAS) AF: 0.00 AC: 0 AN: 83548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106454

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.065
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.67	N
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.20
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.86	P
Vest4		0.49
MutPred		0.48		Loss of catalytic residue at P106 (P = 0.0383)
MVP		0.49
MPC		1.1
ClinPred		0.81	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.83
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs986598114; hg19: chr2-190640307; COSMIC: COSV106417384; COSMIC: COSV106417384;