dbSNP rs5742925: ORMDL1:c.-118+280G>T (chr2-189783989-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001371388.1(ORMDL1):c.-118G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 152,596 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.018 ( 96 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 0 hom. )

Consequence

ORMDL1
NM_001371388.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.18

Variant links:

Genes affected

ORMDL1 (HGNC:16036): (ORMDL sphingolipid biosynthesis regulator 1) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ORMDL1 links:

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

PMS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-189783989-C-A is Benign according to our data. Variant chr2-189783989-C-A is described in ClinVar as [Benign]. Clinvar id is 1292649.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ORMDL1	NM_016467.5 link	c.-118+280G>T		intron_variant	Intron 1 of 4	ENST00000392349.9	NP_057551.1	Q9P0S3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ORMDL1	ENST00000392349.9 link	c.-118+280G>T		intron_variant	Intron 1 of 4	1	NM_016467.5	ENSP00000376160.4		Q9P0S3

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2761

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0632

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00622

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0144

GnomAD4 exome

AF:

0.00336

AC:

AN:

298

Hom.:

AF XY:

0.00400

AC XY:

AN XY:

250

show subpopulations

Gnomad4 AFR exome

AF:

0.167

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0182

AC:

2770

AN:

152298

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1318

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0632

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00775

Hom.:

Bravo

AF:

0.0207

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.5

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over