9-127936603-T-A

Variant names:

• chr9-127936603-T-A
• rs779093563
• NM_003863.4:c.146A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 6P and 4B. PM2 PP3_Strong BS1

The NM_003863.4(DPM2):​c.146A>T​(p.Tyr49Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,391,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y49C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DPM2 NM_003863.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• Publications: 0 publications found

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]

DPM2 Gene-Disease associations (from GenCC):

• congenital muscular dystrophy with intellectual disability and severe epilepsy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000227218 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000144 (2/1391038) while in subpopulation AMR AF = 0.0000577 (2/34648). AF 95% confidence interval is 0.00000956. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003863.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM2	NM_003863.4	MANE Select	c.146A>T	p.Tyr49Phe	missense	Exon 3 of 4	NP_003854.1	O94777
	DPM2	NM_001378437.1		c.56A>T	p.Tyr19Phe	missense	Exon 2 of 3	NP_001365366.1
	DPM2	NR_165631.1		n.303A>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM2	ENST00000314392.13	TSL:1 MANE Select	c.146A>T	p.Tyr49Phe	missense	Exon 3 of 4	ENSP00000322181.8	O94777
	DPM2	ENST00000470181.1	TSL:1	n.438A>T		non_coding_transcript_exon	Exon 2 of 3
	DPM2	ENST00000495270.1	TSL:1	n.930A>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391038 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 684782

African (AFR) AF: 0.00 AC: 0 AN: 31026

American (AMR) AF: 0.0000577 AC: 2 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21904

East Asian (EAS) AF: 0.00 AC: 0 AN: 37942

South Asian (SAS) AF: 0.00 AC: 0 AN: 76366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075260

Other (OTH) AF: 0.00 AC: 0 AN: 57318

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.099	T
PhyloP100		5.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.022	D
Sift4G	Benign	0.095	T
Polyphen		1.0	D
Vest4		0.66
MutPred		0.88		Loss of catalytic residue at Y49 (P = 0.037)
MVP		0.79
MPC		1.5
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.66
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs779093563; hg19: chr9-130698882;