chr2-189784590-G-C

Variant names:

• chr2-189784590-G-C
• rs5742933
• NM_000534.5:c.-24G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000534.5(PMS1):​c.-24G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 153,002 control chromosomes in the GnomAD database, including 4,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4226 hom., cov: 33)
  • Exomes 𝑓: 0.18 (11 hom.)
• Consequence: PMS1 NM_000534.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.285
• Publications: 42 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-189784590-G-C is Benign according to our data. Variant chr2-189784590-G-C is described in ClinVar as Benign. ClinVar VariationId is 1292222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	NM_000534.5	MANE Select	c.-24G>C		5_prime_UTR	Exon 1 of 13	NP_000525.1
	PMS1	NM_001321045.2		c.-150G>C		5_prime_UTR	Exon 1 of 14	NP_001307974.1
	PMS1	NM_001321047.2		c.-201G>C		5_prime_UTR	Exon 1 of 13	NP_001307976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.-24G>C		5_prime_UTR	Exon 1 of 13	ENSP00000406490.3
	PMS1	ENST00000374826.8	TSL:1	c.-24G>C		5_prime_UTR	Exon 1 of 5	ENSP00000363959.4
	PMS1	ENST00000342075.8	TSL:2	n.-24G>C		non_coding_transcript_exon	Exon 1 of 12	ENSP00000343888.4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34723 AN: 152102 Hom.: 4218 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.179 AC: 140 AN: 782 Hom.: 11 Cov.: 0 AF XY: 0.162 AC XY: 69 AN XY: 426

African (AFR) AF: 0.500 AC: 11 AN: 22

American (AMR) AF: 0.250 AC: 4 AN: 16

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 4 AN: 20

East Asian (EAS) AF: 0.0882 AC: 6 AN: 68

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.190 AC: 11 AN: 58

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

European-Non Finnish (NFE) AF: 0.178 AC: 96 AN: 540

Other (OTH) AF: 0.146 AC: 7 AN: 48

GnomAD4 genome AF: 0.228 AC: 34750 AN: 152220 Hom.: 4226 Cov.: 33 AF XY: 0.226 AC XY: 16796 AN XY: 74440

African (AFR) AF: 0.296 AC: 12285 AN: 41522

American (AMR) AF: 0.252 AC: 3849 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 741 AN: 3472

East Asian (EAS) AF: 0.226 AC: 1166 AN: 5170

South Asian (SAS) AF: 0.120 AC: 582 AN: 4830

European-Finnish (FIN) AF: 0.194 AC: 2060 AN: 10594

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13400 AN: 68014

Other (OTH) AF: 0.221 AC: 468 AN: 2114

Alfa AF: 0.134 Hom.: 254

Bravo AF: 0.236

Asia WGS AF: 0.201 AC: 699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.76
PhyloP100		0.28
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs5742933; hg19: chr2-190649316; COSMIC: COSV57877498; COSMIC: COSV57877498;