rs749433780

Variant names:

• chrX-134807653-G-A
• rs749433780
• NM_001388447.1:c.55G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001388447.1(PABIR3):​c.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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 Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: PABIR3 NM_001388447.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.659
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04583028).
• BP6: Variant X-134807653-G-A is Benign according to our data. Variant chrX-134807653-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2607015.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR3	NM_001388447.1	c.55G>A	p.Ala19Thr	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	c.55G>A	p.Ala19Thr	missense_variant	Exon 2 of 11		NM_001388447.1	ENSP00000496338.1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111680 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180819 AF XY: 0.00

Gnomad AFR exome AF: 0.0000766

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 Cov.: 30

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111680 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33858

African (AFR) AF: 0.0000326 AC: 1 AN: 30683

American (AMR) AF: 0.00 AC: 0 AN: 10508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6031

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53122

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 28, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.036
DANN	Benign	0.86
DEOGEN2	Benign	0.0044	.;.;.;.;.;.;T;.;T;T;.;.
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.59	.;T;T;T;T;T;T;T;.;T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	.;.;.;.;.;.;N;N;.;.;.;.
PhyloP100		-0.66
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.60	.;.;N;.;.;.;N;N;.;.;.;.
REVEL	Benign	0.019
Sift	Benign	0.40	.;.;T;.;.;.;T;T;.;.;.;.
Sift4G	Benign	0.36	.;.;T;.;.;T;T;T;.;.;.;.
Polyphen		0.0030, 0.0020	.;.;.;.;.;.;B;B;.;.;.;.
Vest4		0.044, 0.059, 0.031, 0.026
MVP		0.43
MPC		0.16
ClinPred		0.041	T
GERP RS		-3.4
PromoterAI		-0.22	Neutral
Varity_R		0.043
gMVP		0.12
Mutation Taster		=96/4	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: rs749433780; hg19: chrX-133941683; COSMIC: COSV66194420;