rs4065275

Variant names:

• chr17-39924612-A-G
• rs4065275
• NM_139280.4:c.-22-387T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-39924612-A-G
• chr17-39924612-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139280.4(ORMDL3):​c.-22-387T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 185,784 control chromosomes in the GnomAD database, including 29,175 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (24070 hom., cov: 32)
  • Exomes 𝑓: 0.54 (5105 hom.)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226
• Publications: 72 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL3	NM_139280.4	c.-22-387T>C		intron_variant	Intron 1 of 3	ENST00000304046.7	NP_644809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORMDL3	ENST00000304046.7	c.-22-387T>C		intron_variant	Intron 1 of 3	1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5	c.-17-392T>C		intron_variant	Intron 1 of 3	1		ENSP00000464693.1
ORMDL3	ENST00000394169.5	c.-23+143T>C		intron_variant	Intron 3 of 5	2		ENSP00000377724.1
ORMDL3	ENST00000584000.1	c.-22-387T>C		intron_variant	Intron 1 of 3	4		ENSP00000464298.1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 84998 AN: 151874 Hom.: 24063 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.536 AC: 18127 AN: 33792 Hom.: 5105 AF XY: 0.539 AC XY: 9772 AN XY: 18142

African (AFR) AF: 0.607 AC: 728 AN: 1200

American (AMR) AF: 0.609 AC: 1817 AN: 2986

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 468 AN: 852

East Asian (EAS) AF: 0.731 AC: 1098 AN: 1502

South Asian (SAS) AF: 0.562 AC: 2235 AN: 3976

European-Finnish (FIN) AF: 0.466 AC: 442 AN: 948

Middle Eastern (MID) AF: 0.583 AC: 70 AN: 120

European-Non Finnish (NFE) AF: 0.505 AC: 10313 AN: 20406

Other (OTH) AF: 0.531 AC: 956 AN: 1802

GnomAD4 genome AF: 0.559 AC: 85030 AN: 151992 Hom.: 24070 Cov.: 32 AF XY: 0.558 AC XY: 41494 AN XY: 74298

African (AFR) AF: 0.631 AC: 26139 AN: 41438

American (AMR) AF: 0.578 AC: 8824 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1873 AN: 3470

East Asian (EAS) AF: 0.721 AC: 3717 AN: 5154

South Asian (SAS) AF: 0.573 AC: 2764 AN: 4826

European-Finnish (FIN) AF: 0.452 AC: 4776 AN: 10572

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35228 AN: 67940

Other (OTH) AF: 0.565 AC: 1192 AN: 2110

Alfa AF: 0.531 Hom.: 15419

Bravo AF: 0.579

Asia WGS AF: 0.586 AC: 2040 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.72
PhyloP100		0.23
PromoterAI		0.022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4065275; hg19: chr17-38080865;