rs374865650

Variant names:

• chr17-39924143-C-T
• rs374865650
• NM_139280.4:c.61G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39924143-C-T
• chr17-39924143-C-A
• chr17-39924143-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_139280.4(ORMDL3):​c.61G>A​(p.Gly21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,613,974 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: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• BS2: High AC in GnomAd4 at 7 AD gene.

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.61G>A	p.Gly21Ser	missense	Exon 2 of 4	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320801.2		c.61G>A	p.Gly21Ser	missense	Exon 4 of 6	NP_001307730.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.61G>A	p.Gly21Ser	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.61G>A	p.Gly21Ser	missense	Exon 2 of 4	ENSP00000304858.2	Q8N138-1
	ORMDL3	ENST00000579695.5	TSL:1	c.61G>A	p.Gly21Ser	missense	Exon 2 of 4	ENSP00000464693.1	Q8N138-1
	ORMDL3	ENST00000584220.5	TSL:1	c.61G>A	p.Gly21Ser	missense	Exon 1 of 3	ENSP00000464455.1	Q8N138-4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152204 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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 250978 AF XY: 0.0000516

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: 0.0000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1111940

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.00

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.95
MVP		0.51
MPC		1.8
ClinPred		0.96	D
GERP RS		6.0
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.81
gMVP		0.98
Mutation Taster		=56/44	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

dbSNP: rs374865650; hg19: chr17-38080396;