6-31741212-A-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_172166.4(MSH5):āc.197A>Gā(p.Tyr66Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,612,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 0.000031 ( 0 hom. )
Consequence
MSH5
NM_172166.4 missense
NM_172166.4 missense
Scores
3
8
5
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]
MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH5 | NM_172166.4 | c.197A>G | p.Tyr66Cys | missense_variant | 3/25 | ENST00000375750.9 | NP_751898.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH5 | ENST00000375750.9 | c.197A>G | p.Tyr66Cys | missense_variant | 3/25 | 1 | NM_172166.4 | ENSP00000364903.3 | ||
MSH5-SAPCD1 | ENST00000493662.6 | n.197A>G | non_coding_transcript_exon_variant | 3/29 | 1 | ENSP00000417871.2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151972Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
1
AN:
151972
Hom.:
Cov.:
31
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:
GnomAD3 exomes AF: 0.0000284 AC: 7AN: 246712Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134464
GnomAD3 exomes
AF:
AC:
7
AN:
246712
Hom.:
AF XY:
AC XY:
5
AN XY:
134464
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1460762Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 726696
GnomAD4 exome
AF:
AC:
46
AN:
1460762
Hom.:
Cov.:
32
AF XY:
AC XY:
21
AN XY:
726696
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151972Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74230
GnomAD4 genome
AF:
AC:
1
AN:
151972
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74230
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 24, 2023 | The c.197A>G (p.Y66C) alteration is located in exon 3 (coding exon 2) of the MSH5 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the tyrosine (Y) at amino acid position 66 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;.;D;D
Vest4
MutPred
Loss of phosphorylation at Y66 (P = 0.0388);Loss of phosphorylation at Y66 (P = 0.0388);Loss of phosphorylation at Y66 (P = 0.0388);Loss of phosphorylation at Y66 (P = 0.0388);Loss of phosphorylation at Y66 (P = 0.0388);
MVP
MPC
1.5
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