Variant 13-19647025-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000361479.10(MPHOSPH8):c.952A>T(p.Met318Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,605,382 control chromosomes in the GnomAD database, including 4 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: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 4 hom. )

Consequence

MPHOSPH8
ENST00000361479.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.394

Variant links:

Genes affected

MPHOSPH8 (HGNC:29810): (M-phase phosphoprotein 8) Enables chromatin binding activity and methylated histone binding activity. Involved in negative regulation of single stranded viral RNA replication via double stranded DNA intermediate; regulation of DNA methylation; and regulation of gene expression. Located in several cellular components, including cytosol; heterochromatin; and nuclear lumen. Part of nucleosome. [provided by Alliance of Genome Resources, Apr 2022]

MPHOSPH8 links:

MPHOSPH8 (HGNC:):

MPHOSPH8 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015612721).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPHOSPH8	NM_017520.4 linkuse as main transcript	c.952A>T	p.Met318Leu	missense_variant	3/14	ENST00000361479.10	NP_059990.2	Q99549-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPHOSPH8	ENST00000361479.10 linkuse as main transcript	c.952A>T	p.Met318Leu	missense_variant	3/14	1	NM_017520.4	ENSP00000355388.4		Q99549-1
MPHOSPH8	ENST00000414242.3 linkuse as main transcript	c.271A>T	p.Met91Leu	missense_variant	1/3	1		ENSP00000414663.3		A0A0A0MT47

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000573

AC:

139

AN:

242754

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

131898

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.000252

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000667

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000954

Gnomad OTH exome

AF:

0.000697

GnomAD4 exome

AF:

0.00114

AC:

1655

AN:

1453126

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

789

AN XY:

723522

show subpopulations

Gnomad4 AFR exome

AF:

0.000155

Gnomad4 AMR exome

AF:

0.000314

Gnomad4 ASJ exome

AF:

0.00133

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000467

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00137

Gnomad4 OTH exome

AF:

0.00129

GnomAD4 genome

AF:

0.000611

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000828

Hom.:

Bravo

AF:

0.000725

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00160

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

Sep 17, 2021

The c.952A>T (p.M318L) alteration is located in exon 3 (coding exon 3) of the MPHOSPH8 gene. This alteration results from a A to T substitution at nucleotide position 952, causing the methionine (M) at amino acid position 318 to be replaced by a leucine (L). 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

0.078

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.087

DANN

Benign

0.37

DEOGEN2

Benign

0.0020

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.17

M_CAP

Benign

0.0023

MetaRNN

Benign

0.016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.13

REVEL

Benign

0.011

Sift

Benign

0.61

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.16

MutPred

0.36

Loss of catalytic residue at M318 (P = 0.0064);

MVP

0.21

MPC

0.22

ClinPred

0.0011

GERP RS

-5.9

Varity_R

0.031

gMVP

0.011

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over