Genetic Variant PABIR3:p.Ser244Tyr (chrX-134854135-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001388447.1(PABIR3):c.731C>A(p.Ser244Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,097,655 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 6 hem. )

Consequence

PABIR3
NM_001388447.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09

Publications

0 publications found

Variant links:

Genes affected

PABIR3 (HGNC:25202): (PABIR family member 3) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

PABIR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08245179).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1 link	c.731C>A	p.Ser244Tyr	missense_variant	Exon 11 of 11	ENST00000645433.2	NP_001375376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR3	ENST00000645433.2 link	c.731C>A	p.Ser244Tyr	missense_variant	Exon 11 of 11		NM_001388447.1	ENSP00000496338.1		A0A2R8Y7S4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182677

AF XY:

0.0000298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1097655

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363023

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.00

AC:

AN:

54053

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40497

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

841752

Other (OTH)

AF:

0.00

AC:

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.487C>A (p.L163I) alteration is located in exon 7 (coding exon 7) of the FAM122C gene. This alteration results from a C to A substitution at nucleotide position 487, causing the leucine (L) at amino acid position 163 to be replaced by an isoleucine (I). 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

Benign

0.087

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0079

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.33

M_CAP

Benign

0.035

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

2.1

PrimateAI

Benign

0.21

PROVEAN

Benign

0.010

REVEL

Benign

0.056

Sift

Pathogenic

0.0

Sift4G

Benign

0.36

Polyphen

0.73

Vest4

0.098

MutPred

0.20

Loss of catalytic residue at L163 (P = 0.097);

MVP

0.17

MPC

0.19

ClinPred

0.12

GERP RS

3.0

Varity_R

0.16

gMVP

0.020

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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X-134854135-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over