19-4345763-G-C

Variant names:

• chr19-4345763-G-C
• rs747283158
• NM_001300862.2:c.313G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001300862.2(MPND):​c.313G>C​(p.Asp105His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D105N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MPND NM_001300862.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.02
• Publications: 0 publications found

Genes affected

MPND (HGNC:25934): (MPN domain containing) Predicted to enable histone binding activity; peptidase activity; and transcription coactivator activity. Predicted to be involved in chromatin remodeling and positive regulation of transcription by RNA polymerase II. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300862.2. 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
	MPND	NM_001300862.2	MANE Select	c.313G>C	p.Asp105His	missense	Exon 3 of 13	NP_001287791.1	W4VSR2
	MPND	NM_032868.6		c.313G>C	p.Asp105His	missense	Exon 3 of 12	NP_116257.2
	MPND	NM_001159846.3		c.313G>C	p.Asp105His	missense	Exon 3 of 11	NP_001153318.1	Q8N594-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPND	ENST00000599840.6	TSL:5 MANE Select	c.313G>C	p.Asp105His	missense	Exon 3 of 13	ENSP00000471735.1	W4VSR2
	MPND	ENST00000262966.12	TSL:1	c.313G>C	p.Asp105His	missense	Exon 3 of 12	ENSP00000262966.7	Q8N594-1
	MPND	ENST00000594716.5	TSL:1	n.313G>C		non_coding_transcript_exon	Exon 3 of 12	ENSP00000470987.1	M0R044

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461566 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111922

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.54		Gain of helix (P = 0.0854)
MVP		0.25
MPC		1.4
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.66
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747283158; hg19: chr19-4345760;