rs147021156

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001040108.2(MLH3):​c.2670G>A​(p.Met890Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.0690
Variant links:
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004767835).
BP6
Variant 14-75046986-C-T is Benign according to our data. Variant chr14-75046986-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478029.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00088 (134/152344) while in subpopulation AFR AF= 0.00315 (131/41568). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MLH3NM_001040108.2 linkuse as main transcriptc.2670G>A p.Met890Ile missense_variant 2/13 ENST00000355774.7 NP_001035197.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLH3ENST00000355774.7 linkuse as main transcriptc.2670G>A p.Met890Ile missense_variant 2/135 NM_001040108.2 ENSP00000348020 P1Q9UHC1-1
MLH3ENST00000380968.6 linkuse as main transcriptc.2670G>A p.Met890Ile missense_variant 2/121 ENSP00000370355 Q9UHC1-2
MLH3ENST00000556257.5 linkuse as main transcriptc.2670G>A p.Met890Ile missense_variant 2/75 ENSP00000451540
MLH3ENST00000555671.1 linkuse as main transcriptn.216G>A non_coding_transcript_exon_variant 1/25

Frequencies

GnomAD3 genomes
AF:
0.000880
AC:
134
AN:
152226
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00316
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000175
AC:
44
AN:
251214
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00240
Gnomad AMR exome
AF:
0.0000289
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000698
AC:
102
AN:
1461828
Hom.:
0
Cov.:
34
AF XY:
0.0000550
AC XY:
40
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00242
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000880
AC:
134
AN:
152344
Hom.:
0
Cov.:
32
AF XY:
0.000966
AC XY:
72
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.00315
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000120
Hom.:
1
Bravo
AF:
0.000733
ESP6500AA
AF:
0.00204
AC:
9
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000181
AC:
22
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024- -
MLH3-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 10, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.40
DANN
Benign
0.66
DEOGEN2
Benign
0.081
T;.;.;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.78
T;T;T;.
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.0048
T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.4
L;L;.;L
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.32
N;.;N;N
REVEL
Benign
0.062
Sift
Benign
0.12
T;.;T;T
Sift4G
Benign
0.41
T;T;T;T
Polyphen
0.070
B;B;.;B
Vest4
0.059
MutPred
0.34
Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);
MVP
0.56
MPC
0.11
ClinPred
0.0027
T
GERP RS
0.47
Varity_R
0.069
gMVP
0.14

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.

Other links and lift over

dbSNP: rs147021156; hg19: chr14-75513689; API