rs377057828
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002440.4(MSH4):c.223C>A(p.Pro75Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000361 in 1,605,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
MSH4
NM_002440.4 missense
NM_002440.4 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.172
Publications
0 publications found
Genes affected
MSH4 (HGNC:7327): (mutS homolog 4) This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]
MSH4 Gene-Disease associations (from GenCC):
- premature ovarian failure 20Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.121379554).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
5
AN:
152204
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000131 AC: 3AN: 228196 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
228196
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000365 AC: 53AN: 1453430Hom.: 0 Cov.: 31 AF XY: 0.0000305 AC XY: 22AN XY: 722342 show subpopulations
GnomAD4 exome
AF:
AC:
53
AN:
1453430
Hom.:
Cov.:
31
AF XY:
AC XY:
22
AN XY:
722342
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33390
American (AMR)
AF:
AC:
0
AN:
43180
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25868
East Asian (EAS)
AF:
AC:
0
AN:
39480
South Asian (SAS)
AF:
AC:
0
AN:
85082
European-Finnish (FIN)
AF:
AC:
0
AN:
52466
Middle Eastern (MID)
AF:
AC:
0
AN:
5574
European-Non Finnish (NFE)
AF:
AC:
47
AN:
1108338
Other (OTH)
AF:
AC:
6
AN:
60052
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362 show subpopulations
GnomAD4 genome
AF:
AC:
5
AN:
152204
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74362
show subpopulations
African (AFR)
AF:
AC:
1
AN:
41454
American (AMR)
AF:
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5172
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
4
AN:
68046
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.435
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
May 31, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The c.223C>A (p.P75T) alteration is located in exon 1 (coding exon 1) of the MSH4 gene. This alteration results from a C to A substitution at nucleotide position 223, causing the proline (P) at amino acid position 75 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
D
Sift4G
Benign
T
Polyphen
B
Vest4
MVP
MPC
ClinPred
T
GERP RS
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
Publications
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