6-83191204-A-T

Variant names:

• chr6-83191204-A-T
• rs73749738
• NM_015599.3:c.-2-190T>A

Variant summary

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

The NM_001199917.2(PGM3):​c.65T>A​(p.Val22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,534,568 control chromosomes in the GnomAD database, including 494 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.030 (164 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (330 hom.)
• Consequence: PGM3 NM_001199917.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380
• Publications: 6 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]

PGM3 Gene-Disease associations (from GenCC):

• immunodeficiency 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019480586).
• BP6: Variant 6-83191204-A-T is Benign according to our data. Variant chr6-83191204-A-T is described in ClinVar as Benign. ClinVar VariationId is 475004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199917.2. 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.-2-190T>A		intron	N/A	NP_056414.1
	PGM3	NM_001199917.2		c.65T>A	p.Val22Asp	missense	Exon 2 of 14	NP_001186846.1
	PGM3	NM_001367287.1		c.65T>A	p.Val22Asp	missense	Exon 2 of 14	NP_001354216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	ENST00000513973.6	TSL:1 MANE Select	c.-2-190T>A		intron	N/A	ENSP00000424874.1
	PGM3	ENST00000512866.5	TSL:1	c.-2-190T>A		intron	N/A	ENSP00000421565.1
	PGM3	ENST00000283977.9	TSL:5	c.-40+1975T>A		intron	N/A	ENSP00000283977.5

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4490 AN: 151994 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.0811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0838

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0202 AC: 2637 AN: 130380 AF XY: 0.0204

Gnomad AFR exome AF: 0.0900

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0830

Gnomad FIN exome AF: 0.000368

Gnomad NFE exome AF: 0.000983

Gnomad OTH exome AF: 0.00870

GnomAD4 exome AF: 0.00725 AC: 10023 AN: 1382456 Hom.: 330 Cov.: 30 AF XY: 0.00785 AC XY: 5357 AN XY: 682220

African (AFR) AF: 0.0870 AC: 2745 AN: 31546

American (AMR) AF: 0.0153 AC: 548 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25178

East Asian (EAS) AF: 0.0686 AC: 2449 AN: 35714

South Asian (SAS) AF: 0.0330 AC: 2614 AN: 79206

European-Finnish (FIN) AF: 0.000418 AC: 14 AN: 33522

Middle Eastern (MID) AF: 0.0111 AC: 63 AN: 5696

European-Non Finnish (NFE) AF: 0.000709 AC: 764 AN: 1078038

Other (OTH) AF: 0.0143 AC: 825 AN: 57854

GnomAD4 genome AF: 0.0296 AC: 4502 AN: 152112 Hom.: 164 Cov.: 32 AF XY: 0.0300 AC XY: 2228 AN XY: 74348

African (AFR) AF: 0.0811 AC: 3363 AN: 41458

American (AMR) AF: 0.0270 AC: 413 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0839 AC: 432 AN: 5152

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4822

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10596

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68008

Other (OTH) AF: 0.0265 AC: 56 AN: 2112

Alfa AF: 0.00481 Hom.: 17

Bravo AF: 0.0327

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0107 AC: 461

Asia WGS AF: 0.0620 AC: 214 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.5
DANN	Benign	0.56
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.038
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.076
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.069
MPC		0.32
ClinPred		0.0050	T
GERP RS		-0.79
gMVP		0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs73749738; hg19: chr6-83900923; COSMIC: COSV107311759; COSMIC: COSV107311759;