chr10-97432357-C-T

Variant names:

• chr10-97432357-C-T
• rs756333282
• NM_002629.4:c.598C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002629.4(PGAM1):​c.598C>T​(p.Leu200Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000267 in 1,611,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. L200V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: PGAM1 NM_002629.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1083349).
• BS2: High AC in GnomAdExome4 at 40 AD gene.

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.598C>T	p.Leu200Phe	missense splice_region	Exon 4 of 4	NP_002620.1	P18669
	PGAM1	NM_001317079.2		c.553C>T	p.Leu185Phe	missense splice_region	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.598C>T	p.Leu200Phe	missense splice_region	Exon 4 of 4	ENSP00000359991.4	P18669
	PGAM1	ENST00000889729.1		c.562C>T	p.Leu188Phe	missense splice_region	Exon 4 of 4	ENSP00000559788.1
	PGAM1	ENST00000940113.1		c.541C>T	p.Leu181Phe	missense splice_region	Exon 4 of 4	ENSP00000610172.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251390 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459806 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726202

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.000827 AC: 37 AN: 44714

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: 86164

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4150

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60212

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000988 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.037	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.48
Sift	Benign	0.037	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.41		Gain of sheet (P = 0.1208)
MVP		0.66
MPC		1.1
ClinPred		0.26	T
GERP RS		5.5
Varity_R		0.58
gMVP		0.57
Mutation Taster		=50/50

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: rs756333282; hg19: chr10-99192114;