rs117175017

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003859.3(DPM1):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,936 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 5 hom. )

Consequence

DPM1
NM_003859.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

DPM1 (HGNC:3005): (dolichyl-phosphate mannosyltransferase subunit 1, catalytic) Dolichol-phosphate mannose (Dol-P-Man) serves as a donor of mannosyl residues on the lumenal side of the endoplasmic reticulum (ER). Lack of Dol-P-Man results in defective surface expression of GPI-anchored proteins. Dol-P-Man is synthesized from GDP-mannose and dolichol-phosphate on the cytosolic side of the ER by the enzyme dolichyl-phosphate mannosyltransferase. Human DPM1 lacks a carboxy-terminal transmembrane domain and signal sequence and is regulated by DPM2. Mutations in this gene are associated with congenital disorder of glycosylation type Ie. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

DPM1 links:

DPM1 (HGNC:):

DPM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006441295).

BP6

Variant 20-50958484-G-A is Benign according to our data. Variant chr20-50958484-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00161 (245/152236) while in subpopulation NFE AF= 0.00246 (167/68004). AF 95% confidence interval is 0.00215. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPM1	NM_003859.3 linkuse as main transcript	c.40C>T	p.Arg14Trp	missense_variant	1/9	ENST00000371588.10	NP_003850.1	O60762A0A0S2Z4Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPM1	ENST00000371588.10 linkuse as main transcript	c.40C>T	p.Arg14Trp	missense_variant	1/9	1	NM_003859.3	ENSP00000360644.5		O60762

Frequencies

GnomAD3 genomes

AF:

0.00161

AC:

245

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00246

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00164

AC:

412

AN:

251296

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00298

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00279

AC:

4080

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00272

AC XY:

1979

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00248

Gnomad4 NFE exome

AF:

0.00337

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.00161

AC:

245

AN:

152236

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

109

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00246

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DPM1: BP4, BP5, BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DPM1 p.Arg14Trp variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs117175017) and ClinVar (reported as likely benign by Invitae and a VUS by Illumina and GeneDx for Congenital disorder of glycosylation type 1E). The variant was identified in control databases in 472 of 282680 chromosomes (1 homozygous) at a frequency of 0.00167 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 71 of 24980 chromosomes (freq: 0.002842), European (non-Finnish) in 327 of 129138 chromosomes (freq: 0.002532), Other in 15 of 7226 chromosomes (freq: 0.002076), Latino in 47 of 35440 chromosomes (freq: 0.001326) and African in 12 of 24956 chromosomes (freq: 0.000481); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant occurs outside of the splicing consensus sequence and four out of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a greater than 10% difference in splicing. The p.Arg14 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Congenital disorder of glycosylation type 1E

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 21, 2017

A variant of uncertain significance has been identified in the DPM1 gene. The R14W variant has been previously reported in the heterozygous state in an individual with antithrombin deficiency, ventricular septal defect and scoliosis who also harbored homozygous variants in the ALG12 gene. The authors suggest a diagnosis of CDG due to the homozygous ALG12 variants identified in this individual (de la Morena-Barrio et al., 2016). The R14W variant is observed in 154/66626 (0.23%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.92

N;N;N

REVEL

Benign

0.046

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.12

T;T;D

Polyphen

0.0

B;.;.

Vest4

0.27

MVP

0.54

MPC

0.27

ClinPred

0.075

GERP RS

2.4

Varity_R

0.070

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over