rs73307962

Positions:

• chr17-39924973-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139280.4(ORMDL3):​c.-22-748A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 152,142 control chromosomes in the GnomAD database, including 96 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 0.018 (96 hom., cov: 32)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORMDL3	NM_139280.4	c.-22-748A>C		intron_variant		ENST00000304046.7	NP_644809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORMDL3	ENST00000304046.7	c.-22-748A>C		intron_variant		1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5	c.-17-753A>C		intron_variant		1		ENSP00000464693.1
ORMDL3	ENST00000394169.5	c.-73-168A>C		intron_variant		2		ENSP00000377724.1
ORMDL3	ENST00000584000.1	c.-22-748A>C		intron_variant		4		ENSP00000464298.1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2675 AN: 152024 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0176 AC: 2683 AN: 152142 Hom.: 96 Cov.: 32 AF XY: 0.0172 AC XY: 1282 AN XY: 74398

Gnomad4 AFR AF: 0.0611

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0112 Hom.: 8

Bravo AF: 0.0202

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.77
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs73307962; hg19: chr17-38081226;