13-19633947-A-T

Variant names:

• chr13-19633947-A-T
• rs554482845
• NM_017520.4:c.199A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017520.4(MPHOSPH8):​c.199A>T​(p.Met67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MPHOSPH8 NM_017520.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1757778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPHOSPH8	NM_017520.4	c.199A>T	p.Met67Leu	missense_variant	Exon 1 of 14	ENST00000361479.10	NP_059990.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPHOSPH8	ENST00000361479.10	c.199A>T	p.Met67Leu	missense_variant	Exon 1 of 14	1	NM_017520.4	ENSP00000355388.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237780 Hom.: 0 AF XY: 0.00000779 AC XY: 1 AN XY: 128370

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: 0.0000346

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456634 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723908

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.78	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.092
Sift	Benign	0.099	T
Sift4G	Benign	0.12	T
Polyphen		0.27	B
Vest4		0.33
MutPred		0.61		Loss of MoRF binding (P = 0.0849);
MVP		0.50
MPC		0.34
ClinPred		0.33	T
GERP RS		2.2
Varity_R		0.55
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs554482845; hg19: chr13-20208087;