dbSNP rs550407834: PMS1:c.418+78G>A (chr2-189805832-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001321049.2(PMS1):c.496G>A(p.Gly166Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,582,372 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

PMS1
NM_001321049.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: -1.25

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010663331).

BP6

Variant 2-189805832-G-A is Benign according to our data. Variant chr2-189805832-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 133375.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 86 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321049.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMS1	NM_000534.5	MANE Select	c.418+78G>A		intron	N/A	NP_000525.1	P54277-1
PMS1	NM_001321049.2		c.496G>A	p.Gly166Ser	missense	Exon 4 of 4	NP_001307978.1	E9PC40
PMS1	NM_001321045.2		c.418+78G>A		intron	N/A	NP_001307974.1	P54277-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PMS1	ENST00000441310.7	TSL:1 MANE Select	c.418+78G>A	intron	N/A	ENSP00000406490.3	P54277-1
PMS1	ENST00000374826.8	TSL:1	c.418+78G>A	intron	N/A	ENSP00000363959.4	Q5XG96
PMS1	ENST00000424059.1	TSL:1	n.418+78G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000560

AC:

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000291

AC:

AN:

199036

AF XY:

0.000261

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.000732

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.000775

GnomAD4 exome

AF:

0.000237

AC:

339

AN:

1430564

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

190

AN XY:

709074

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

32490

American (AMR)

AF:

0.000656

AC:

AN:

41150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25666

East Asian (EAS)

AF:

0.00

AC:

AN:

38280

South Asian (SAS)

AF:

0.00

AC:

AN:

83438

European-Finnish (FIN)

AF:

0.0000386

AC:

AN:

51798

Middle Eastern (MID)

AF:

0.00213

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.000209

AC:

228

AN:

1093094

Other (OTH)

AF:

0.000542

AC:

AN:

59018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000567

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

41410

American (AMR)

AF:

0.000394

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000955

AC:

AN:

10472

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67916

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000512

Hom.:

Bravo

AF:

0.000684

ExAC

AF:

0.000269

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PMS1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.51

CADD

Benign

1.9

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0094

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.29

M_CAP

Benign

0.025

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.69

PhyloP100

-1.3

PROVEAN

Benign

1.3

REVEL

Benign

0.13

Sift

Benign

0.46

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.066

MVP

0.85

ClinPred

0.0019

GERP RS

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over