Genetic Variant NM_138333.5:c.103T>A (chr9-68780267-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_138333.5(PABIR1):c.103T>A(p.Ser35Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000383 in 1,566,296 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PABIR1
NM_138333.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

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]

PABIR1 links:

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]

PIP5K1B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity PBIR1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41866168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR1	NM_138333.5 link	c.103T>A	p.Ser35Thr	missense_variant	Exon 1 of 1	ENST00000394264.7	NP_612206.5	Q96E09B3KX07
PIP5K1B	NM_003558.4 link	c.-86+37610T>A		intron_variant	Intron 2 of 15	ENST00000265382.8	NP_003549.1	O14986-1Q7KYT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PABIR1	ENST00000394264.7 link	c.103T>A	p.Ser35Thr	missense_variant	Exon 1 of 1	6	NM_138333.5	ENSP00000377807.5	Q96E09
PIP5K1B	ENST00000265382.8 link	c.-86+37610T>A		intron_variant	Intron 2 of 15	1	NM_003558.4	ENSP00000265382.2	O14986-1
PIP5K1B	ENST00000478500.3 link	n.-86+37610T>A		intron_variant	Intron 2 of 20	1		ENSP00000435778.1	O14986-2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1414496

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

700338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103T>A (p.S35T) alteration is located in exon 1 (coding exon 1) of the FAM122A gene. This alteration results from a T to A substitution at nucleotide position 103, causing the serine (S) at amino acid position 35 to be replaced by a threonine (T). 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

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.33

PrimateAI

Pathogenic

0.84

REVEL

Benign

0.18

MVP

0.32

MPC

1.5

ClinPred

0.97

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over