rs117175017

Variant names:

• chr20-50958484-G-A
• rs117175017
• NM_003859.3:c.40C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-50958484-G-A
• chr20-50958484-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R14R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: DPM1 NM_003859.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.78
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type 1E

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 338758.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPM1	NM_003859.3	c.40C>T	p.Arg14Trp	missense_variant	Exon 1 of 9	ENST00000371588.10	NP_003850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPM1	ENST00000371588.10	c.40C>T	p.Arg14Trp	missense_variant	Exon 1 of 9	1	NM_003859.3	ENSP00000360644.5

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152118 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00164 AC: 412 AN: 251296 AF XY: 0.00164

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 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.: 5 Cov.: 32 AF XY: 0.00272 AC XY: 1979 AN XY: 727162

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00145 AC: 65 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00248 AC: 132 AN: 53232

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00337 AC: 3750 AN: 1112008

Other (OTH) AF: 0.00192 AC: 116 AN: 60394

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152236 Hom.: 1 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74450

African (AFR) AF: 0.000457 AC: 19 AN: 41548

American (AMR) AF: 0.00118 AC: 18 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00246 AC: 167 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00211 Hom.: 2

Bravo AF: 0.00150

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00163 AC: 198

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPM1: BP4, BP5, BS1 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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:1 Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 21, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.
PhyloP100		1.8
PrimateAI	Benign	0.39	T
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	T
GERP RS		2.4
PromoterAI		-0.16	Neutral
Varity_R		0.070
gMVP		0.69
Mutation Taster		=100/0	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: rs117175017; hg19: chr20-49575021;