chr2-189784514-G-T

Variant names:

• chr2-189784514-G-T
• rs5742932
• NM_000534.5:c.-100G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000534.5(PMS1):​c.-100G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 152,984 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (335 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: PMS1 NM_000534.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0220
• Publications: 3 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 -10 ACMG points.

• BP6: Variant 2-189784514-G-T is Benign according to our data. Variant chr2-189784514-G-T is described in ClinVar as Benign. ClinVar VariationId is 1221371.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	NM_000534.5	MANE Select	c.-100G>T		5_prime_UTR	Exon 1 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.-226G>T		5_prime_UTR	Exon 1 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.-277G>T		5_prime_UTR	Exon 1 of 13	NP_001307976.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.-100G>T		5_prime_UTR	Exon 1 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.-100G>T		5_prime_UTR	Exon 1 of 5	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000921104.1		c.-100G>T		5_prime_UTR	Exon 1 of 14	ENSP00000591163.1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5424 AN: 152196 Hom.: 335 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0297

GnomAD4 exome AF: 0.00149 AC: 1 AN: 670 Hom.: 0 Cov.: 0 AF XY: 0.00216 AC XY: 1 AN XY: 464

African (AFR) AF: 0.0556 AC: 1 AN: 18

American (AMR) AF: 0.00 AC: 0 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12

East Asian (EAS) AF: 0.00 AC: 0 AN: 30

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 534

Other (OTH) AF: 0.00 AC: 0 AN: 32

GnomAD4 genome AF: 0.0357 AC: 5435 AN: 152314 Hom.: 335 Cov.: 33 AF XY: 0.0339 AC XY: 2524 AN XY: 74496

African (AFR) AF: 0.124 AC: 5166 AN: 41550

American (AMR) AF: 0.0118 AC: 181 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0111 Hom.: 30

Bravo AF: 0.0407

Asia WGS AF: 0.00722 AC: 26 AN: 3478

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	-0.78
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		-0.022
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 18

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

Other links and lift over

dbSNP: rs5742932; hg19: chr2-190649240;