rs7997

chr9-127935750-G-Cchr9-127935750-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003863.4(DPM2):c.227C>G(p.Thr76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,610,654 control chromosomes in the GnomAD database, including 567,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48010 hom., cov: 32)
  • Exomes 𝑓: 0.84 (519404 hom.)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0340

Genes affected

DPM2 (HGNC:3006): (dolichyl-phosphate mannosyltransferase subunit 2, regulatory) 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. The protein encoded by this gene is a hydrophobic protein that contains 2 predicted transmembrane domains and a putative ER localization signal near the C terminus. This protein associates with DPM1 in vivo and is required for the ER localization and stable expression of DPM1 and also enhances the binding of dolichol-phosphate to DPM1. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.1462935E-7).
• BP6: Variant 9-127935750-G-C is Benign according to our data. Variant chr9-127935750-G-C is described in ClinVar as [Benign]. Clinvar id is 128921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127935750-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPM2	NM_003863.4	c.227C>G	p.Thr76Ser	missense_variant	4/4	ENST00000314392.13
DPM2	NM_001378437.1	c.137C>G	p.Thr46Ser	missense_variant	3/3
DPM2	NR_165631.1	n.384C>G		non_coding_transcript_exon_variant	4/4
DPM2	NR_165632.1	n.68C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPM2	ENST00000314392.13	c.227C>G	p.Thr76Ser	missense_variant	4/4	1	NM_003863.4	P1
	ENST00000592240.5	n.143+1105G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.787 AC: 119613 AN: 151924 Hom.: 47973 Cov.: 32

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.869

Gnomad MID AF: 0.752

Gnomad NFE AF: 0.872

Gnomad OTH AF: 0.783

GnomAD3 exomes AF: 0.789 AC: 197919 AN: 250700 Hom.: 79920 AF XY: 0.791 AC XY: 107164 AN XY: 135504

Gnomad AFR exome AF: 0.667

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.459

Gnomad SAS exome AF: 0.704

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.800

GnomAD4 exome AF: 0.839 AC: 1223461 AN: 1458610 Hom.: 519404 Cov.: 51 AF XY: 0.835 AC XY: 606011 AN XY: 725692

Gnomad4 AFR exome AF: 0.675

Gnomad4 AMR exome AF: 0.815

Gnomad4 ASJ exome AF: 0.726

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.705

Gnomad4 FIN exome AF: 0.867

Gnomad4 NFE exome AF: 0.873

Gnomad4 OTH exome AF: 0.809

GnomAD4 genome AF: 0.787 AC: 119698 AN: 152044 Hom.: 48010 Cov.: 32 AF XY: 0.783 AC XY: 58165 AN XY: 74312

Gnomad4 AFR AF: 0.672

Gnomad4 AMR AF: 0.819

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.869

Gnomad4 NFE AF: 0.872

Gnomad4 OTH AF: 0.785

Alfa AF: 0.835 Hom.: 37159

Bravo AF: 0.778

TwinsUK AF: 0.865 AC: 3209

ALSPAC AF: 0.861 AC: 3317

ESP6500AA AF: 0.680 AC: 2996

ESP6500EA AF: 0.868 AC: 7466

ExAC AF: 0.787 AC: 95556

Asia WGS AF: 0.617 AC: 2148 AN: 3478

EpiCase AF: 0.855

EpiControl AF: 0.856

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital muscular dystrophy with intellectual disability and severe epilepsy Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.86
Dann	Benign	0.75
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0306);
MPC		0.55
ClinPred		0.0023	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7997; hg19: chr9-130698029; COSMIC: COSV58709021; COSMIC: COSV58709021;