rs953965111

Variant names:

• chr12-132710937-G-A
• rs953965111
• NM_001170543.2:c.61G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-132710937-G-A
• chr12-132710937-G-C

Variant summary

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

The NM_001170543.2(PGAM5):​c.61G>A​(p.Val21Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,170,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V21L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: PGAM5 NM_001170543.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

PGAM5 (HGNC:28763): (PGAM family member 5, mitochondrial serine/threonine protein phosphatase) Enables GTPase activator activity and protein serine/threonine phosphatase activity. Involved in necroptotic process. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000256632 (HGNC:):

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=0.37620902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM5	NM_001170543.2	c.61G>A	p.Val21Met	missense_variant	Exon 1 of 6	ENST00000498926.7	NP_001164014.1
PGAM5	NM_001170544.2	c.61G>A	p.Val21Met	missense_variant	Exon 1 of 6		NP_001164015.1
PGAM5	NM_138575.4	c.61G>A	p.Val21Met	missense_variant	Exon 1 of 6		NP_612642.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM5	ENST00000498926.7	c.61G>A	p.Val21Met	missense_variant	Exon 1 of 6	2	NM_001170543.2	ENSP00000438465.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150332 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000445

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1550 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000980 AC: 10 AN: 1019996 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 8 AN XY: 481596

African (AFR) AF: 0.00 AC: 0 AN: 20434

American (AMR) AF: 0.00 AC: 0 AN: 6464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11544

East Asian (EAS) AF: 0.00 AC: 0 AN: 20010

South Asian (SAS) AF: 0.00 AC: 0 AN: 19342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2602

European-Non Finnish (NFE) AF: 0.00000907 AC: 8 AN: 882268

Other (OTH) AF: 0.0000513 AC: 2 AN: 39014

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150332 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73358

African (AFR) AF: 0.00 AC: 0 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67356

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61G>A (p.V21M) alteration is located in exon 1 (coding exon 1) of the PGAM5 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the valine (V) at amino acid position 21 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.86	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		1.5
PrimateAI	Pathogenic	0.98	D
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.083
Sift	Benign	0.18	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.99	D;D
Vest4		0.34
MutPred		0.37		Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.29
MPC		1.3
ClinPred		0.53	D
GERP RS		2.7
PromoterAI		0.28	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.085
gMVP		0.27
Mutation Taster		=91/9	polymorphism

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

Publications

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Other links and lift over

dbSNP: rs953965111; hg19: chr12-133287523;