6-83191204-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199917.2(PGM3):​c.65T>C​(p.Val22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000978 in 1,534,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: PGM3 NM_001199917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04755017).

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>C		intron	N/A	NP_056414.1
	PGM3	NM_001199917.2		c.65T>C	p.Val22Ala	missense	Exon 2 of 14	NP_001186846.1
	PGM3	NM_001367287.1		c.65T>C	p.Val22Ala	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>C		intron	N/A	ENSP00000424874.1
	PGM3	ENST00000512866.5	TSL:1	c.-2-190T>C		intron	N/A	ENSP00000421565.1
	PGM3	ENST00000283977.9	TSL:5	c.-40+1975T>C		intron	N/A	ENSP00000283977.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000153 AC: 2 AN: 130380 AF XY: 0.0000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000868 AC: 12 AN: 1382508 Hom.: 0 Cov.: 30 AF XY: 0.00000586 AC XY: 4 AN XY: 682240

African (AFR) AF: 0.00 AC: 0 AN: 31560

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1078042

Other (OTH) AF: 0.0000518 AC: 3 AN: 57866

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41354

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 17

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.9
DANN	Benign	0.62
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.038
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.027
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.055	T
Vest4		0.18
MutPred		0.44		Loss of stability (P = 0.0472)
MVP		0.030
MPC		0.23
ClinPred		0.030	T
GERP RS		-0.79
gMVP		0.50
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;