chr9-68780562-C-G

Variant names:

• chr9-68780562-C-G
• rs546322647
• NM_138333.5:c.398C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138333.5(PABIR1):​c.398C>G​(p.Ser133Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S133T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PABIR1 NM_138333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66
• Publications: 0 publications found

Genes affected

PABIR1 (HGNC:23490): (PP2A Aalpha (PPP2R1A) and B55A (PPP2R2A) interacting phosphatase regulator 1) Enables protein serine/threonine phosphatase inhibitor activity. Involved in mitotic G2/M transition checkpoint; positive regulation of cell growth; and positive regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PIP5K1B (HGNC:8995): (phosphatidylinositol-4-phosphate 5-kinase type 1 beta) Predicted to enable 1-phosphatidylinositol-4-phosphate 5-kinase activity. Predicted to be involved in regulation of phosphatidylinositol 3-kinase signaling. Predicted to act upstream of or within phosphatidylinositol biosynthetic process. Located in uropod. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138333.5. 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
	PABIR1	NM_138333.5	MANE Select	c.398C>G	p.Ser133Cys	missense	Exon 1 of 1	NP_612206.5
	PIP5K1B	NM_003558.4	MANE Select	c.-85-37899C>G		intron	N/A	NP_003549.1	O14986-1
	PIP5K1B	NM_001376036.1		c.-85-37899C>G		intron	N/A	NP_001362965.1	O14986-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABIR1	ENST00000394264.7	TSL:6 MANE Select	c.398C>G	p.Ser133Cys	missense	Exon 1 of 1	ENSP00000377807.5	Q96E09
	PIP5K1B	ENST00000265382.8	TSL:1 MANE Select	c.-85-37899C>G		intron	N/A	ENSP00000265382.2	O14986-1
	PIP5K1B	ENST00000478500.3	TSL:1	n.-85-37899C>G		intron	N/A	ENSP00000435778.1	O14986-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251460 AF XY: 0.00000736

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: 0.00000547 AC: 8 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

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	Benign	0.12
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.043	T
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
REVEL	Uncertain	0.55
MVP		0.24
MPC		1.7
ClinPred		0.98	D
GERP RS		4.2
PromoterAI		-0.12	Neutral
gMVP		0.64
Mutation Taster		=52/48	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

Other links and lift over

dbSNP: rs546322647; hg19: chr9-71395478;