chr13-19647025-A-T

Variant names:

• chr13-19647025-A-T
• rs141397171
• NM_017520.4:c.952A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017520.4(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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M318I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: MPHOSPH8 NM_017520.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.394
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015612721).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017520.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPHOSPH8	NM_017520.4	MANE Select	c.952A>T	p.Met318Leu	missense	Exon 3 of 14	NP_059990.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPHOSPH8	ENST00000361479.10	TSL:1 MANE Select	c.952A>T	p.Met318Leu	missense	Exon 3 of 14	ENSP00000355388.4	Q99549-1
	MPHOSPH8	ENST00000414242.3	TSL:1	c.271A>T	p.Met91Leu	missense	Exon 1 of 3	ENSP00000414663.3	A0A0A0MT47
	MPHOSPH8	ENST00000971230.1		c.952A>T	p.Met318Leu	missense	Exon 3 of 15	ENSP00000641289.1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152138 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000573 AC: 139 AN: 242754 AF XY: 0.000538

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 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.: 4 Cov.: 32 AF XY: 0.00109 AC XY: 789 AN XY: 723522

African (AFR) AF: 0.000155 AC: 5 AN: 32316

American (AMR) AF: 0.000314 AC: 13 AN: 41376

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 34 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85720

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00137 AC: 1521 AN: 1109788

Other (OTH) AF: 0.00129 AC: 77 AN: 59750

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74440

African (AFR) AF: 0.000265 AC: 11 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000828 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000818

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.087
DANN	Benign	0.37
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.39
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.011
Sift	Benign	0.61	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.36		Loss of catalytic residue at M318 (P = 0.0064)
MVP		0.21
MPC		0.22
ClinPred		0.0011	T
GERP RS		-5.9
PromoterAI		-0.018	Neutral
Varity_R		0.031
gMVP		0.011
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs141397171; hg19: chr13-20221165;