chr14-24214070-G-T

Variant names:

• chr14-24214070-G-T
• rs755822554
• NM_138476.4:c.485C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138476.4(MDP1):​c.485C>A​(p.Thr162Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign 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. T162S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MDP1 NM_138476.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 publications found

Genes affected

MDP1 (HGNC:28781): (magnesium dependent phosphatase 1) Predicted to enable acid phosphatase activity. Predicted to be involved in fructosamine metabolic process and peptidyl-tyrosine dephosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000260669 (HGNC:):

NEDD8-MDP1 (HGNC:39551): (NEDD8-MDP1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) and MDP1 (magnesium-dependent phosphatase 1) genes on chromosome 14. One of the read-through transcripts on this locus encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Jul 2016]

CHMP4A (HGNC:20274): (charged multivesicular body protein 4A) CHMP4A belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06915614).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138476.4. 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
	MDP1	NM_138476.4	MANE Select	c.485C>A	p.Thr162Asn	missense	Exon 6 of 6	NP_612485.2
	NEDD8-MDP1	NM_001199823.3		c.536C>A	p.Thr179Asn	missense	Exon 7 of 7	NP_001186752.1
	MDP1	NM_001199821.2		c.345C>A	p.Asn115Lys	missense	Exon 5 of 5	NP_001186750.1	Q86V88-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDP1	ENST00000288087.12	TSL:1 MANE Select	c.485C>A	p.Thr162Asn	missense	Exon 6 of 6	ENSP00000288087.7	Q86V88-1
	MDP1	ENST00000396833.2	TSL:1	c.345C>A	p.Asn115Lys	missense	Exon 5 of 5	ENSP00000380045.2	Q86V88-3
	ENSG00000260669	ENST00000565988.1	TSL:1	n.578C>A		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460778 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726658

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111498

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.96
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.079	N
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Benign	0.15	N
REVEL	Benign	0.012
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.27
MutPred		0.31		Gain of methylation at N115 (P = 0.0105)
MVP		0.067
ClinPred		0.052	T
GERP RS		-0.74
Varity_R		0.060
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: rs755822554; hg19: chr14-24683276;