rs473267

Variant names:

• chr6-83170448-C-T
• rs473267
• NM_015599.3:c.1396G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015599.3(PGM3):​c.1396G>A​(p.Asp466Asn) variant causes a missense change. The variant allele was found at a frequency of 0.273 in 1,612,928 control chromosomes in the GnomAD database, including 64,262 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D466D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.34 (10368 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53894 hom.)
• Consequence: PGM3 NM_015599.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.61
• Publications: 45 publications found

Genes affected

PGM3 (HGNC:8907): (phosphoglucomutase 3) This gene encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. A non-synonymous single nucleotide polymorphism in this gene may play a role in resistance to diabetic nephropathy and neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

DOP1A (HGNC:21194): (DOP1 leucine zipper like protein A) Predicted to be involved in Golgi to endosome transport and endoplasmic reticulum organization. Predicted to be located in Golgi membrane. Predicted to be active in endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

DOP1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9459846E-5).
• BP6: Variant 6-83170448-C-T is Benign according to our data. Variant chr6-83170448-C-T is described in ClinVar as Benign. ClinVar VariationId is 681218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015599.3. 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
	PGM3	NM_015599.3	MANE Select	c.1396G>A	p.Asp466Asn	missense	Exon 12 of 13	NP_056414.1	O95394-1
	PGM3	NM_001199917.2		c.1480G>A	p.Asp494Asn	missense	Exon 13 of 14	NP_001186846.1	O95394-4
	PGM3	NM_001367287.1		c.1480G>A	p.Asp494Asn	missense	Exon 13 of 14	NP_001354216.1	O95394-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	ENST00000513973.6	TSL:1 MANE Select	c.1396G>A	p.Asp466Asn	missense	Exon 12 of 13	ENSP00000424874.1	O95394-1
	PGM3	ENST00000512866.5	TSL:1	c.1396G>A	p.Asp466Asn	missense	Exon 12 of 14	ENSP00000421565.1	O95394-3
	PGM3	ENST00000283977.9	TSL:5	c.1153G>A	p.Asp385Asn	missense	Exon 11 of 12	ENSP00000283977.5	J3KN95

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52127 AN: 151870 Hom.: 10327 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.274 AC: 68811 AN: 251322 AF XY: 0.266

Gnomad AFR exome AF: 0.564

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.266 AC: 388225 AN: 1460940 Hom.: 53894 Cov.: 32 AF XY: 0.263 AC XY: 191331 AN XY: 726838

African (AFR) AF: 0.569 AC: 19044 AN: 33448

American (AMR) AF: 0.258 AC: 11551 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5092 AN: 26128

East Asian (EAS) AF: 0.306 AC: 12154 AN: 39684

South Asian (SAS) AF: 0.235 AC: 20298 AN: 86238

European-Finnish (FIN) AF: 0.265 AC: 14136 AN: 53418

Middle Eastern (MID) AF: 0.216 AC: 1243 AN: 5766

European-Non Finnish (NFE) AF: 0.259 AC: 288018 AN: 1111176

Other (OTH) AF: 0.276 AC: 16689 AN: 60360

GnomAD4 genome AF: 0.344 AC: 52221 AN: 151988 Hom.: 10368 Cov.: 32 AF XY: 0.341 AC XY: 25365 AN XY: 74302

African (AFR) AF: 0.553 AC: 22911 AN: 41406

American (AMR) AF: 0.307 AC: 4688 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 682 AN: 3468

East Asian (EAS) AF: 0.316 AC: 1634 AN: 5174

South Asian (SAS) AF: 0.231 AC: 1112 AN: 4824

European-Finnish (FIN) AF: 0.266 AC: 2809 AN: 10572

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17503 AN: 67952

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.282 Hom.: 22811

Bravo AF: 0.353

TwinsUK AF: 0.253 AC: 939

ALSPAC AF: 0.258 AC: 993

ESP6500AA AF: 0.548 AC: 2414

ESP6500EA AF: 0.253 AC: 2174

ExAC AF: 0.278 AC: 33764

Asia WGS AF: 0.284 AC: 988 AN: 3478

EpiCase AF: 0.245

EpiControl AF: 0.245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 23 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.000059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.6
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Benign	0.17	T
Sift4G	Benign	0.31	T
Polyphen		0.24	B
Vest4		0.15
MPC		0.33
ClinPred		0.031	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.70
Mutation Taster		=97/3	polymorphism (auto)

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: rs473267; hg19: chr6-83880167; COSMIC: COSV52283001; COSMIC: COSV52283001;