NM_016467.5:c.-118+291C>G

Variant names:

• chr2-189783978-G-C
• rs5742924
• NM_016467.5:c.-118+291C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016467.5(ORMDL1):​c.-118+291C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 152,352 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (155 hom., cov: 33)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: ORMDL1 NM_016467.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.827
• Publications: 4 publications found

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]

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-189783978-G-C is Benign according to our data. Variant chr2-189783978-G-C is described in ClinVar as Benign. ClinVar VariationId is 1248274.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016467.5. 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
	ORMDL1	NM_016467.5	MANE Select	c.-118+291C>G		intron	N/A	NP_057551.1	Q9P0S3
	ORMDL1	NM_001371388.1		c.-107C>G		5_prime_UTR	Exon 1 of 4	NP_001358317.1
	ORMDL1	NM_001371385.1		c.-8+291C>G		intron	N/A	NP_001358314.1	A0ABB0MVM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL1	ENST00000392349.9	TSL:1 MANE Select	c.-118+291C>G		intron	N/A	ENSP00000376160.4	Q9P0S3
	ORMDL1	ENST00000392350.7	TSL:1	c.-8+291C>G		intron	N/A	ENSP00000376161.3	Q9P0S3
	ORMDL1	ENST00000853748.1		c.-217C>G		5_prime_UTR	Exon 1 of 5	ENSP00000523807.1

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5736 AN: 152154 Hom.: 157 Cov.: 33

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0450

GnomAD4 exome AF: 0.0250 AC: 2 AN: 80 Hom.: 0 AF XY: 0.0303 AC XY: 2 AN XY: 66

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0147 AC: 1 AN: 68

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0377 AC: 5734 AN: 152272 Hom.: 155 Cov.: 33 AF XY: 0.0391 AC XY: 2908 AN XY: 74442

African (AFR) AF: 0.0668 AC: 2777 AN: 41558

American (AMR) AF: 0.0268 AC: 410 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.0279 AC: 144 AN: 5162

South Asian (SAS) AF: 0.0512 AC: 247 AN: 4824

European-Finnish (FIN) AF: 0.0515 AC: 547 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0205 AC: 1393 AN: 68024

Other (OTH) AF: 0.0441 AC: 93 AN: 2110

Alfa AF: 0.0269 Hom.: 13

Bravo AF: 0.0371

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.38
PhyloP100		0.83
PromoterAI		0.068	Neutral
Mutation Taster		=100/0	polymorphism

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: rs5742924; hg19: chr2-190648704;