2-189775575-G-C

Variant names:

• chr2-189775575-G-C
• rs2047675209
• NM_016467.5:c.316C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016467.5(ORMDL1):​c.316C>G​(p.Pro106Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ORMDL1 NM_016467.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL1	NM_016467.5	c.316C>G	p.Pro106Ala	missense_variant	Exon 4 of 5	ENST00000392349.9	NP_057551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORMDL1	ENST00000392349.9	c.316C>G	p.Pro106Ala	missense_variant	Exon 4 of 5	1	NM_016467.5	ENSP00000376160.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447492 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719650

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.316C>G (p.P106A) alteration is located in exon 4 (coding exon 2) of the ORMDL1 gene. This alteration results from a C to G substitution at nucleotide position 316, causing the proline (P) at amino acid position 106 to be replaced by an alanine (A). 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	0.77
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D;D;D;D;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;D;.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.5	M;M;M;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.91
MutPred		0.91		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.66
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs2047675209; hg19: chr2-190640301;