rs1145232

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000534.5(PMS1):c.1501G>A(p.Gly501Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0027 in 1,613,614 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.013 ( 37 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 33 hom. )

Consequence

PMS1
NM_000534.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 6.02

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:

LOC105373796 (HGNC:):

LOC105373796 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004475683).

BP6

Variant 2-189854773-G-A is Benign according to our data. Variant chr2-189854773-G-A is described in ClinVar as [Benign]. Clinvar id is 135054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1975/152132) while in subpopulation AFR AF= 0.0445 (1847/41494). AF 95% confidence interval is 0.0428. There are 37 homozygotes in gnomad4. There are 946 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 37 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5 link	c.1501G>A	p.Gly501Arg	missense_variant	Exon 9 of 13	ENST00000441310.7	NP_000525.1	P54277-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7 link	c.1501G>A	p.Gly501Arg	missense_variant	Exon 9 of 13	1	NM_000534.5	ENSP00000406490.3		P54277-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1962

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0443

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.00379

AC:

947

AN:

249904

Hom.:

AF XY:

0.00306

AC XY:

415

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.00397

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000584

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00163

AC:

2389

AN:

1461482

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1054

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.0445

Gnomad4 AMR exome

AF:

0.00412

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000407

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.0130

AC:

1975

AN:

152132

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

946

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0445

Gnomad4 AMR

AF:

0.00393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.0148

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0417

AC:

183

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.00435

AC:

528

Asia WGS

AF:

0.00260

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

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

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;D;D;D;D;D;T;D

MetaRNN

Benign

0.0045

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

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.6

.;.;.;.;M;.;M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.2

.;.;D;.;D;D;D;D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

.;.;D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;D;.;.;.;.

Vest4

0.48, 0.48, 0.52, 0.44, 0.48, 0.47

MutPred

0.73

.;.;.;.;Loss of helix (P = 0.0072);.;Loss of helix (P = 0.0072);.;.;

MVP

1.0

MPC

0.28

ClinPred

0.041

GERP RS

4.8

Varity_R

0.85

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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