14-24214070-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138476.4(MDP1):​c.485C>T​(p.Thr162Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 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)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051200777).

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>T	p.Thr162Ile	missense	Exon 6 of 6	NP_612485.2
	NEDD8-MDP1	NM_001199823.3		c.536C>T	p.Thr179Ile	missense	Exon 7 of 7	NP_001186752.1
	MDP1	NM_001199821.2		c.345C>T	p.Asn115Asn	synonymous	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>T	p.Thr162Ile	missense	Exon 6 of 6	ENSP00000288087.7	Q86V88-1
	MDP1	ENST00000396833.2	TSL:1	c.345C>T	p.Asn115Asn	synonymous	Exon 5 of 5	ENSP00000380045.2	Q86V88-3
	ENSG00000260669	ENST00000565988.1	TSL:1	n.578C>T		non_coding_transcript_exon	Exon 5 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.070	N
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.018
Sift	Benign	0.049	D
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.32		Gain of catalytic residue at P164 (P = 0.0077)
MVP		0.17
MPC		0.15
ClinPred		0.13	T
GERP RS		-0.74
Varity_R		0.037
gMVP		0.034
Mutation Taster		=99/1	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; COSMIC: COSV51660037; COSMIC: COSV51660037;