NM_016467.5:c.88G>A

Variant names:

• chr2-189782508-C-T
• rs761768957
• NM_016467.5:c.88G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016467.5(ORMDL1):​c.88G>A​(p.Val30Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ORMDL1 NM_016467.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12090525).

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.88G>A	p.Val30Ile	missense	Exon 3 of 5	NP_057551.1	Q9P0S3
	ORMDL1	NM_001371385.1		c.88G>A	p.Val30Ile	missense	Exon 2 of 5	NP_001358314.1	A0ABB0MVM0
	ORMDL1	NM_001371386.1		c.88G>A	p.Val30Ile	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.88G>A	p.Val30Ile	missense	Exon 3 of 5	ENSP00000376160.4	Q9P0S3
	ORMDL1	ENST00000325795.7	TSL:1	c.88G>A	p.Val30Ile	missense	Exon 1 of 3	ENSP00000326869.3	Q9P0S3
	ORMDL1	ENST00000392350.7	TSL:1	c.88G>A	p.Val30Ile	missense	Exon 2 of 4	ENSP00000376161.3	Q9P0S3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251480 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000114836), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.081
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.73
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		5.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.29
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.31
MutPred		0.54		Loss of MoRF binding (P = 0.1996)
MVP		0.27
MPC		0.31
ClinPred		0.070	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.80
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs761768957; hg19: chr2-190647234;