rs3169572

Positions:

• chr17-39921159-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_139280.4(ORMDL3):​c.*1391C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 152,922 control chromosomes in the GnomAD database, including 75 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 0.027 (74 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1 hom.)
• Consequence: ORMDL3 NM_139280.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138

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=-0.6).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0272 (4136/152288) while in subpopulation NFE AF= 0.0416 (2828/68018). AF 95% confidence interval is 0.0403. There are 74 homozygotes in gnomad4. There are 1952 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4136 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ORMDL3	NM_139280.4	c.*1391C>T		3_prime_UTR_variant	4/4	ENST00000304046.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ORMDL3	ENST00000304046.7	c.*1391C>T		3_prime_UTR_variant	4/4	1	NM_139280.4	P1
ORMDL3	ENST00000579695.5	c.*1391C>T		3_prime_UTR_variant	4/4	1		P1
ORMDL3	ENST00000579287.1	n.233C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4137 AN: 152170 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0272

GnomAD4 exome AF: 0.0410 AC: 26 AN: 634 Hom.: 1 Cov.: 0 AF XY: 0.0408 AC XY: 16 AN XY: 392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.0415

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0272 AC: 4136 AN: 152288 Hom.: 74 Cov.: 33 AF XY: 0.0262 AC XY: 1952 AN XY: 74456

Gnomad4 AFR AF: 0.00760

Gnomad4 AMR AF: 0.0217

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0408

Gnomad4 NFE AF: 0.0416

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0359 Hom.: 25

Bravo AF: 0.0243

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs3169572; hg19: chr17-38077412;