14-24214337-G-A

Variant names:

• chr14-24214337-G-A
• rs2295317
• NM_138476.4:c.376C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138476.4(MDP1):​c.376C>T​(p.Arg126Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MDP1 NM_138476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDP1	NM_138476.4	c.376C>T	p.Arg126Trp	missense_variant	Exon 5 of 6	ENST00000288087.12	NP_612485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDP1	ENST00000288087.12	c.376C>T	p.Arg126Trp	missense_variant	Exon 5 of 6	1	NM_138476.4	ENSP00000288087.7
NEDD8-MDP1	ENST00000534348.5	c.427C>T	p.Arg143Trp	missense_variant	Exon 6 of 7	5		ENSP00000431482.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251474 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74418

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000136 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376C>T (p.R126W) alteration is located in exon 5 (coding exon 5) of the MDP1 gene. This alteration results from a C to T substitution at nucleotide position 376, causing the arginine (R) at amino acid position 126 to be replaced by a tryptophan (W). 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	0.30
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.67	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.72
MVP		0.93
MPC		0.61
ClinPred		0.89	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: -27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2295317; hg19: chr14-24683543;