20-50935230-T-C

Variant names:

• chr20-50935230-T-C
• rs559946698
• NM_003859.3:c.685A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_003859.3(DPM1):​c.685A>G​(p.Ile229Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,585,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: DPM1 NM_003859.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.47
• Publications: 4 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]

ADNP-AS1 (HGNC:51227): (ADNP antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07531884).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000277 (37/133576) while in subpopulation AMR AF = 0.00181 (25/13820). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003859.3. 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
	DPM1	NM_003859.3	MANE Select	c.685A>G	p.Ile229Val	missense	Exon 9 of 9	NP_003850.1	O60762
	DPM1	NM_001317034.1		c.790A>G	p.Ile264Val	missense	Exon 10 of 10	NP_001303963.1	O60762
	DPM1	NM_001317035.1		c.766A>G	p.Ile256Val	missense	Exon 10 of 10	NP_001303964.1	Q5QPK2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPM1	ENST00000371588.10	TSL:1 MANE Select	c.685A>G	p.Ile229Val	missense	Exon 9 of 9	ENSP00000360644.5	O60762
	DPM1	ENST00000371582.8	TSL:1	c.766A>G	p.Ile256Val	missense	Exon 10 of 10	ENSP00000360638.4	Q5QPK2
	DPM1	ENST00000466152.5	TSL:1	n.*140A>G		non_coding_transcript_exon	Exon 9 of 9	ENSP00000507119.1	A0A804HIK9

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 37 AN: 133484 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 30 AN: 248554 AF XY: 0.0000967

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.0000585 AC: 85 AN: 1452346 Hom.: 0 Cov.: 27 AF XY: 0.0000553 AC XY: 40 AN XY: 723214

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.000829 AC: 37 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.0000281 AC: 31 AN: 1104214

Other (OTH) AF: 0.000216 AC: 13 AN: 60076

GnomAD4 genome AF: 0.000277 AC: 37 AN: 133576 Hom.: 0 Cov.: 33 AF XY: 0.000261 AC XY: 17 AN XY: 65096

African (AFR) AF: 0.000174 AC: 5 AN: 28704

American (AMR) AF: 0.00181 AC: 25 AN: 13820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4920

South Asian (SAS) AF: 0.00 AC: 0 AN: 4574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000107 AC: 7 AN: 65498

Other (OTH) AF: 0.00 AC: 0 AN: 1904

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.000729

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Congenital disorder of glycosylation type 1E (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.075	T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.63
MPC		0.26
ClinPred		0.20	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.57
Mutation Taster		=63/37	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: rs559946698; hg19: chr20-49551767;