chr9-127936603-T-A

Position:

• chr9-127936603-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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 Uncertain_significance. Variant got 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. gnomad4_exome 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 gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPM2	NM_003863.4	c.146A>T	p.Tyr49Phe	missense_variant	3/4	ENST00000314392.13	NP_003854.1
DPM2	NM_001378437.1	c.56A>T	p.Tyr19Phe	missense_variant	2/3		NP_001365366.1
DPM2	NR_165631.1	n.303A>T		non_coding_transcript_exon_variant	3/4
DPM2	NR_165632.1	n.38-823A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPM2	ENST00000314392.13	c.146A>T	p.Tyr49Phe	missense_variant	3/4	1	NM_003863.4	ENSP00000322181	P1
	ENST00000592240.5	n.143+1958T>A		intron_variant, non_coding_transcript_variant		5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000577

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.099	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.022	D;T
Sift4G	Benign	0.095	T;T
Polyphen		1.0	D;.
Vest4		0.66
MutPred		0.88		Loss of catalytic residue at Y49 (P = 0.037);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

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: rs779093563; hg19: chr9-130698882;