19-4352954-G-A

Position:

• chr19-4352954-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001300862.2(MPND):​c.589G>A​(p.Val197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,252,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MPND NM_001300862.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837

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]

ENSG00000269807 (HGNC:):

ACMG classification

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=0.046473324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPND	NM_001300862.2	c.589G>A	p.Val197Ile	missense_variant	4/13	ENST00000599840.6	NP_001287791.1
MPND	NM_032868.6	c.589G>A	p.Val197Ile	missense_variant	4/12		NP_116257.2
MPND	NM_001159846.3	c.589G>A	p.Val197Ile	missense_variant	4/11		NP_001153318.1
MPND	XM_006722926.3	c.589G>A	p.Val197Ile	missense_variant	4/13		XP_006722989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPND	ENST00000599840.6	c.589G>A	p.Val197Ile	missense_variant	4/13	5	NM_001300862.2	ENSP00000471735.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000231 AC: 29 AN: 1252746 Hom.: 0 Cov.: 36 AF XY: 0.0000195 AC XY: 12 AN XY: 615334

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000289

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000249 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.589G>A (p.V197I) alteration is located in exon 4 (coding exon 4) of the MPND gene. This alteration results from a G to A substitution at nucleotide position 589, causing the valine (V) at amino acid position 197 to be replaced by an isoleucine (I). 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	0.067
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.0052	T;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.046	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.51	N;N;.;.
REVEL	Benign	0.031
Sift	Benign	0.17	T;T;.;.
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.0080	B;B;.;.
Vest4		0.039
MutPred		0.12		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);.;
MVP		0.16
MPC		0.33
ClinPred		0.020	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.18

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

Other links and lift over

dbSNP: rs749709699; hg19: chr19-4352951;