chr17-39927703-G-T

Variant names:

• chr17-39927703-G-T
• rs78298787
• ENST00000889245.1:c.-23+1103C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The ENST00000889245.1(ORMDL3):​c.-23+1103C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 985,192 control chromosomes in the GnomAD database, including 14 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 0.0064 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (6 hom.)
• Consequence: ORMDL3 ENST00000889245.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.288
• Publications: 3 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]

LRRC3C (HGNC:40034): (leucine rich repeat containing 3C) Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000264968 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00643 (977/151984) while in subpopulation AFR AF = 0.0219 (905/41298). AF 95% confidence interval is 0.0207. There are 8 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 977 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000889245.1. 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
	LRRC3C	NM_001195545.2	MANE Select	c.-286G>T		upstream_gene	N/A	NP_001182474.1	A6NJW4
	ORMDL3	NM_139280.4	MANE Select	c.-242C>A		upstream_gene	N/A	NP_644809.1	Q8N138-1
	ORMDL3	NM_001320802.2		c.-237C>A		upstream_gene	N/A	NP_001307731.1	Q8N138-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL3	ENST00000889245.1		c.-23+1103C>A		intron	N/A	ENSP00000559304.1
	LRRC3C	ENST00000377924.6	TSL:3 MANE Select	c.-286G>T		upstream_gene	N/A	ENSP00000367157.4	A6NJW4
	ORMDL3	ENST00000304046.7	TSL:1 MANE Select	c.-242C>A		upstream_gene	N/A	ENSP00000304858.2	Q8N138-1

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 975 AN: 151866 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000652 AC: 543 AN: 833208 Hom.: 6 Cov.: 30 AF XY: 0.000611 AC XY: 235 AN XY: 384830

African (AFR) AF: 0.0286 AC: 449 AN: 15702

American (AMR) AF: 0.00507 AC: 5 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5154

East Asian (EAS) AF: 0.00 AC: 0 AN: 3632

South Asian (SAS) AF: 0.00 AC: 0 AN: 16476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 278

Middle Eastern (MID) AF: 0.00123 AC: 2 AN: 1624

European-Non Finnish (NFE) AF: 0.0000709 AC: 54 AN: 762068

Other (OTH) AF: 0.00121 AC: 33 AN: 27288

GnomAD4 genome AF: 0.00643 AC: 977 AN: 151984 Hom.: 8 Cov.: 33 AF XY: 0.00657 AC XY: 488 AN XY: 74308

African (AFR) AF: 0.0219 AC: 905 AN: 41298

American (AMR) AF: 0.00327 AC: 50 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68012

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.0119 Hom.: 0

Bravo AF: 0.00729

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.7
DANN	Benign	0.78
PhyloP100		0.29
PromoterAI		0.032	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78298787; hg19: chr17-38083956;