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GeneBe

2-189795777-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_000534.5(PMS1):c.141T>C(p.Tyr47=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,613,002 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 (★).

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 40 hom. )

Consequence

PMS1
NM_000534.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.813
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-189795777-T-C is Benign according to our data. Variant chr2-189795777-T-C is described in ClinVar as [Benign]. Clinvar id is 333200.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.813 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1636/152334) while in subpopulation AFR AF= 0.0375 (1560/41570). AF 95% confidence interval is 0.036. There are 30 homozygotes in gnomad4. There are 767 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 29 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PMS1NM_000534.5 linkuse as main transcriptc.141T>C p.Tyr47= synonymous_variant 3/13 ENST00000441310.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PMS1ENST00000441310.7 linkuse as main transcriptc.141T>C p.Tyr47= synonymous_variant 3/131 NM_000534.5 P1P54277-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0107
AC:
1624
AN:
152216
Hom.:
29
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0373
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00766
GnomAD3 exomes
AF:
0.00277
AC:
696
AN:
251152
Hom.:
14
AF XY:
0.00219
AC XY:
297
AN XY:
135868
show subpopulations
Gnomad AFR exome
AF:
0.0397
Gnomad AMR exome
AF:
0.00133
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.00116
AC:
1690
AN:
1460668
Hom.:
40
Cov.:
30
AF XY:
0.000973
AC XY:
707
AN XY:
726736
show subpopulations
Gnomad4 AFR exome
AF:
0.0418
Gnomad4 AMR exome
AF:
0.00163
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.00320
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0107
AC:
1636
AN:
152334
Hom.:
30
Cov.:
32
AF XY:
0.0103
AC XY:
767
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0375
Gnomad4 AMR
AF:
0.00320
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00758
Alfa
AF:
0.00326
Hom.:
13
Bravo
AF:
0.0123
Asia WGS
AF:
0.00404
AC:
14
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJun 28, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
Cadd
Benign
7.6
Dann
Benign
0.57

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.

Other links and lift over

dbSNP: rs5742980; hg19: chr2-190660503; API