Genetic Variant PABIR3:p.Asp20Glu (chrX-134807658-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.60C>A(p.Asp20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,206,355 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000051 ( 0 hom. 16 hem. )

Consequence

PABIR3
NM_001388447.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.88

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=0.07866588).

BS2

High Hemizygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1 link	c.60C>A	p.Asp20Glu	missense_variant	Exon 2 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.60C>A	p.Asp20Glu	missense_variant	Exon 2 of 11		NM_001388447.1	ENSP00000496338.1		A0A2R8Y7S4

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111711

Hom.:

Cov.:

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000222

AC:

AN:

180226

AF XY:

0.0000463

show subpopulations

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:

0.0000496

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000512

AC:

AN:

1094644

Hom.:

Cov.:

AF XY:

0.0000444

AC XY:

AN XY:

360346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26336

American (AMR)

AF:

0.00

AC:

AN:

34970

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19256

East Asian (EAS)

AF:

0.00

AC:

AN:

30046

South Asian (SAS)

AF:

0.00

AC:

AN:

53500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40436

Middle Eastern (MID)

AF:

0.000485

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0000643

AC:

AN:

840051

Other (OTH)

AF:

0.00

AC:

AN:

45927

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111711

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33917

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30673

American (AMR)

AF:

0.00

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.60C>A (p.D20E) alteration is located in exon 1 (coding exon 1) of the FAM122C gene. This alteration results from a C to A substitution at nucleotide position 60, causing the aspartic acid (D) at amino acid position 20 to be replaced by a glutamic acid (E). 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

0.18

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.016

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.021

.;.;.;.;.;.;T;.;T;T;.;.

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.54

.;T;T;T;T;T;T;T;.;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.079

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;.;.;.;.;.;L;L;.;.;.;.

PhyloP100

-2.9

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

.;.;N;.;.;.;N;N;.;.;.;.

REVEL

Benign

0.031

Sift

Benign

0.20

.;.;T;.;.;.;T;T;.;.;.;.

Sift4G

Benign

0.12

.;.;T;.;.;T;T;T;.;.;.;.

Polyphen

0.21, 0.18

.;.;.;.;.;.;B;B;.;.;.;.

Vest4

0.062, 0.053, 0.042, 0.019

MutPred

0.24

.;.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.25

MPC

0.16

ClinPred

0.043

GERP RS

-6.0

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.056

gMVP

0.10

Mutation Taster

=97/3

polymorphism

(source)

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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X-134807658-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