14-24215571-G-A

Position:

• chr14-24215571-G-A

Variant summary

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

The NM_138476.4(MDP1):​c.190C>T​(p.Pro64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,614,112 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (1 hom.)
• Consequence: MDP1 NM_138476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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]

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]

ENSG00000260669 (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=0.00993216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDP1	NM_138476.4	c.190C>T	p.Pro64Ser	missense_variant	3/6	ENST00000288087.12	NP_612485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDP1	ENST00000288087.12	c.190C>T	p.Pro64Ser	missense_variant	3/6	1	NM_138476.4	ENSP00000288087.7
NEDD8-MDP1	ENST00000534348.5	c.241C>T	p.Pro81Ser	missense_variant	4/7	5		ENSP00000431482.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000616 AC: 155 AN: 251426 Hom.: 1 AF XY: 0.000611 AC XY: 83 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000494 AC: 722 AN: 1461878 Hom.: 1 Cov.: 32 AF XY: 0.000495 AC XY: 360 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000890 Hom.: 1

Bravo AF: 0.000397

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00136

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

Oct 21, 2021

The c.190C>T (p.P64S) alteration is located in exon 3 (coding exon 3) of the MDP1 gene. This alteration results from a C to T substitution at nucleotide position 190, causing the proline (P) at amino acid position 64 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.0099	T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.4	L;L;.
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.25
MVP		0.83
MPC		0.13
ClinPred		0.073	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.19

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: rs140361770; hg19: chr14-24684777;