10-97432405-A-G

Variant names:

• chr10-97432405-A-G
• rs567929292
• NM_002629.4:c.646A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002629.4(PGAM1):​c.646A>G​(p.Ile216Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I216L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PGAM1 NM_002629.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.19
• Publications: 0 publications found

Genes affected

PGAM1 (HGNC:8888): (phosphoglycerate mutase 1) The protein encoded by this gene is a mutase that catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

EXOSC1 (HGNC:17286): (exosome component 1) This gene encodes a core component of the exosome. The mammalian exosome is required for rapid degradation of AU rich element-containing RNAs but not for poly(A) shortening. The association of this protein with the exosome is mediated by protein-protein interactions with ribosomal RNA-processing protein 42 and ribosomal RNA-processing protein 46. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2016]

EXOSC1 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 1F

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33053744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002629.4. 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
	PGAM1	NM_002629.4	MANE Select	c.646A>G	p.Ile216Val	missense	Exon 4 of 4	NP_002620.1	P18669
	PGAM1	NM_001317079.2		c.601A>G	p.Ile201Val	missense	Exon 4 of 4	NP_001304008.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAM1	ENST00000334828.6	TSL:1 MANE Select	c.646A>G	p.Ile216Val	missense	Exon 4 of 4	ENSP00000359991.4	P18669
	PGAM1	ENST00000889728.1		c.634A>G	p.Ile212Val	missense	Exon 4 of 4	ENSP00000559787.1
	PGAM1	ENST00000889729.1		c.610A>G	p.Ile204Val	missense	Exon 4 of 4	ENSP00000559788.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1459796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726204

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4154

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.39
Sift	Benign	0.081	T
Sift4G	Uncertain	0.057	T
Polyphen		0.0040	B
Vest4		0.36
MutPred		0.51		Gain of glycosylation at T212 (P = 0.198)
MVP		0.90
MPC		0.92
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.095
gMVP		0.38
Mutation Taster		=48/52	disease causing

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: rs567929292; hg19: chr10-99192162;