rs28937871

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040108.2(MLH3):ā€‹c.1496A>Gā€‹(p.Asn499Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

19

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.447
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.042622).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MLH3NM_001040108.2 linkuse as main transcriptc.1496A>G p.Asn499Ser missense_variant 2/13 ENST00000355774.7 NP_001035197.1 Q9UHC1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MLH3ENST00000355774.7 linkuse as main transcriptc.1496A>G p.Asn499Ser missense_variant 2/135 NM_001040108.2 ENSP00000348020.2 Q9UHC1-1
MLH3ENST00000380968.6 linkuse as main transcriptc.1496A>G p.Asn499Ser missense_variant 2/121 ENSP00000370355.3 Q9UHC1-2
MLH3ENST00000556257.5 linkuse as main transcriptc.1496A>G p.Asn499Ser missense_variant 2/75 ENSP00000451540.1 G3V419

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251212
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461770
Hom.:
0
Cov.:
35
AF XY:
0.00000275
AC XY:
2
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyOMIMApr 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
9.0
DANN
Benign
0.35
DEOGEN2
Benign
0.087
T;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.030
N
LIST_S2
Benign
0.74
T;T;T;.
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.043
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;N;.;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.19
N;.;N;N
REVEL
Benign
0.058
Sift
Benign
0.54
T;.;T;T
Sift4G
Benign
0.35
T;T;T;T
Polyphen
0.0060
B;B;.;B
Vest4
0.042
MutPred
0.50
Gain of catalytic residue at P500 (P = 0.0021);Gain of catalytic residue at P500 (P = 0.0021);Gain of catalytic residue at P500 (P = 0.0021);Gain of catalytic residue at P500 (P = 0.0021);
MVP
0.39
MPC
0.079
ClinPred
0.016
T
GERP RS
-1.7
Varity_R
0.024
gMVP
0.12

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: rs28937871; hg19: chr14-75514863; API