16-82149364-C-T

Variant summary

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

The NM_005792.2(MPHOSPH6):​c.295G>A​(p.Glu99Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,460,664 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

MPHOSPH6
NM_005792.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89
Variant links:
Genes affected
MPHOSPH6 (HGNC:7214): (M-phase phosphoprotein 6) Predicted to enable RNA binding activity. Involved in maturation of 5.8S rRNA. Located in cytosol; nucleolus; and nucleoplasm. Colocalizes with nuclear exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.067996174).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MPHOSPH6NM_005792.2 linkuse as main transcriptc.295G>A p.Glu99Lys missense_variant 4/5 ENST00000258169.9
MPHOSPH6XM_011522808.4 linkuse as main transcriptc.241G>A p.Glu81Lys missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MPHOSPH6ENST00000258169.9 linkuse as main transcriptc.295G>A p.Glu99Lys missense_variant 4/51 NM_005792.2 P1
MPHOSPH6ENST00000563504.5 linkuse as main transcriptc.208G>A p.Glu70Lys missense_variant 4/52
MPHOSPH6ENST00000563100.5 linkuse as main transcriptc.241G>A p.Glu81Lys missense_variant, NMD_transcript_variant 5/75
MPHOSPH6ENST00000568016.1 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000559
AC:
14
AN:
250512
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135482
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:
0.000457
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1460664
Hom.:
1
Cov.:
32
AF XY:
0.0000427
AC XY:
31
AN XY:
726736
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:
0.000475
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
ExAC
AF:
0.0000659
AC:
8

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 submitterclinical testingAmbry GeneticsDec 06, 2021The c.295G>A (p.E99K) alteration is located in exon 4 (coding exon 4) of the MPHOSPH6 gene. This alteration results from a G to A substitution at nucleotide position 295, causing the glutamic acid (E) at amino acid position 99 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
18
DANN
Benign
0.76
DEOGEN2
Benign
0.0057
T;.
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.068
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.095
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.051
Sift
Benign
0.40
T;T
Sift4G
Benign
0.48
T;T
Polyphen
0.0010
B;.
Vest4
0.22
MutPred
0.44
Gain of ubiquitination at E99 (P = 0.0109);.;
MVP
0.34
MPC
0.0017
ClinPred
0.062
T
GERP RS
4.7
Varity_R
0.14
gMVP
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs768439916; hg19: chr16-82182969; COSMIC: COSV50737425; COSMIC: COSV50737425; API