rs1200430585

Variant names:

• chr17-39924098-C-T
• rs1200430585
• NM_139280.4:c.106G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39924098-C-T
• chr17-39924098-C-A

Variant summary

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

The NM_139280.4(ORMDL3):​c.106G>A​(p.Val36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,916 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: 0.0000014 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

Genes affected

ORMDL3 (HGNC:16038): (ORMDL sphingolipid biosynthesis regulator 3) Involved in ceramide metabolic process. Acts upstream of or within several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of SPOTS complex. [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=0.37697184).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139280.4. 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
	ORMDL3	NM_139280.4	MANE Select	c.106G>A	p.Val36Met	missense	Exon 2 of 4	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320801.2		c.106G>A	p.Val36Met	missense	Exon 4 of 6	NP_001307730.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.106G>A	p.Val36Met	missense	Exon 2 of 4	NP_001307731.1	Q8N138-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.106G>A	p.Val36Met	missense	Exon 2 of 4	ENSP00000304858.2	Q8N138-1
	ORMDL3	ENST00000579695.5	TSL:1	c.106G>A	p.Val36Met	missense	Exon 2 of 4	ENSP00000464693.1	Q8N138-1
	ORMDL3	ENST00000584220.5	TSL:1	c.106G>A	p.Val36Met	missense	Exon 1 of 3	ENSP00000464455.1	Q8N138-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 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

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250868 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.14
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.65
MutPred		0.65		Loss of stability (P = 0.0811)
MVP		0.32
MPC		0.86
ClinPred		0.42	T
GERP RS		5.8
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.83

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

dbSNP: rs1200430585; hg19: chr17-38080351;