rs5742926

Variant names:

• chr2-189784079-G-T
• rs5742926
• NM_016467.5:c.-118+190C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-189784079-G-T
• chr2-189784079-G-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_016467.5(ORMDL1):​c.-118+190C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,424 control chromosomes in the GnomAD database, including 1,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1181 hom., cov: 33)
  • Exomes 𝑓: 0.22 (2 hom.)
• Consequence: ORMDL1 NM_016467.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.156
• Publications: 12 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 -16 ACMG points.

• BP6: Variant 2-189784079-G-T is Benign according to our data. Variant chr2-189784079-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 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+190C>A		intron	N/A	NP_057551.1	Q9P0S3
	ORMDL1	NM_001371385.1		c.-8+190C>A		intron	N/A	NP_001358314.1	A0ABB0MVM0
	ORMDL1	NM_001371386.1		c.-118+190C>A		intron	N/A	NP_001358315.1	A0ABB0MVM0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORMDL1	ENST00000392349.9	TSL:1 MANE Select	c.-118+190C>A		intron	N/A	ENSP00000376160.4	Q9P0S3
	ORMDL1	ENST00000392350.7	TSL:1	c.-8+190C>A		intron	N/A	ENSP00000376161.3	Q9P0S3
	ORMDL1	ENST00000853749.1		c.-597C>A		5_prime_UTR	Exon 1 of 5	ENSP00000523808.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17355 AN: 152116 Hom.: 1180 Cov.: 33

Gnomad AFR AF: 0.0546

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0910

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.124

GnomAD4 exome AF: 0.223 AC: 42 AN: 188 Hom.: 2 Cov.: 0 AF XY: 0.216 AC XY: 29 AN XY: 134

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.100 AC: 1 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.247 AC: 39 AN: 158

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.114 AC: 17357 AN: 152236 Hom.: 1181 Cov.: 33 AF XY: 0.112 AC XY: 8349 AN XY: 74430

African (AFR) AF: 0.0546 AC: 2269 AN: 41542

American (AMR) AF: 0.126 AC: 1920 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3472

East Asian (EAS) AF: 0.0910 AC: 470 AN: 5164

South Asian (SAS) AF: 0.0789 AC: 381 AN: 4828

European-Finnish (FIN) AF: 0.114 AC: 1208 AN: 10606

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10041 AN: 68004

Other (OTH) AF: 0.125 AC: 265 AN: 2116

Alfa AF: 0.137 Hom.: 1885

Bravo AF: 0.111

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.6
DANN	Benign	0.70
PhyloP100		0.16
PromoterAI		0.17	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 3

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

Other links and lift over

dbSNP: rs5742926; hg19: chr2-190648805; COSMIC: COSV57877496; COSMIC: COSV57877496;