5-80654728-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_002439.5(MSH3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,446,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000083 ( 0 hom. )
Consequence
MSH3
NM_002439.5 start_lost
NM_002439.5 start_lost
Scores
6
5
5
Clinical Significance
Conservation
PhyloP100: 3.22
Genes affected
MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]
DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH3 | NM_002439.5 | c.1A>G | p.Met1? | start_lost | 1/24 | ENST00000265081.7 | |
DHFR | NM_000791.4 | c.-239T>C | 5_prime_UTR_variant | 1/6 | ENST00000439211.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH3 | ENST00000265081.7 | c.1A>G | p.Met1? | start_lost | 1/24 | 1 | NM_002439.5 | P2 | |
DHFR | ENST00000439211.7 | c.-239T>C | 5_prime_UTR_variant | 1/6 | 1 | NM_000791.4 | P1 | ||
MSH3 | ENST00000667069.1 | c.1A>G | p.Met1? | start_lost | 1/22 | ||||
MSH3 | ENST00000670357.1 | c.1A>G | p.Met1? | start_lost, NMD_transcript_variant | 1/25 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000830 AC: 12AN: 1446040Hom.: 0 Cov.: 35 AF XY: 0.00000973 AC XY: 7AN XY: 719748
GnomAD4 exome
AF:
AC:
12
AN:
1446040
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Cov.:
35
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AC XY:
7
AN XY:
719748
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change affects the initiator methionine of the MSH3 mRNA. The next in-frame methionine is located at codon 115. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 659229). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2023 | The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the MSH3 gene and results from a A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 114 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. Based on internal structural analysis, this variant is not anticipated to result in a decrease in structural stability. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of glycosylation at S2 (P = 0.1276);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at