Variant 2-189795811-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000534.5(PMS1):c.175G>A(p.Glu59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,613,856 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 15 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 2.07

Variant links:

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]

PMS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021964759).

BP6

Variant 2-189795811-G-A is Benign according to our data. Variant chr2-189795811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708165.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5 linkuse as main transcript	c.175G>A	p.Glu59Lys	missense_variant	3/13	ENST00000441310.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7 linkuse as main transcript	c.175G>A	p.Glu59Lys	missense_variant	3/13	1	NM_000534.5	P1	P54277-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00459

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00275

AC:

691

AN:

251432

Hom.:

AF XY:

0.00280

AC XY:

380

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00467

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00383

AC:

5595

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

2773

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.00241

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00147

Gnomad4 FIN exome

AF:

0.00152

Gnomad4 NFE exome

AF:

0.00460

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00250

AC:

380

AN:

152290

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

180

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00459

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00378

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00330

AC:

401

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00308

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PMS1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.19

T;T;T;T;T;.;T;T;.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.020

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.022

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.015

.;.;.;N;.;N;.;.;N;.

MutationTaster

Benign

1.0

D;D;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.74

.;.;.;N;N;N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.51

.;.;.;T;T;T;T;T;T;T

Sift4G

Benign

0.86

.;T;T;T;T;T;T;T;T;T

Polyphen

0.034, 0.0020, 0.0090

.;B;B;B;B;.;.;.;.;.

Vest4

0.27, 0.31, 0.15, 0.32, 0.26, 0.21

MVP

0.91

MPC

0.066

ClinPred

0.0055

GERP RS

4.8

Varity_R

0.074

gMVP

0.35

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

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