X-134781846-C-T

Variant names:

• chrX-134781846-C-T
• rs757171918
• NM_001387468.1:c.634G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001387468.1(PABIR2):​c.634G>A​(p.Ala212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,197,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 86 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A212V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 81 hem.)
• Consequence: PABIR2 NM_001387468.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0950
• Publications: 0 publications found

Genes affected

PABIR2 (HGNC:30490): (PABIR family member 2) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to be part of collagen trimer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043709576).
• BS2: High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABIR2	NM_001387468.1	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 10	ENST00000343004.10	NP_001374397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABIR2	ENST00000343004.10	c.634G>A	p.Ala212Thr	missense_variant	Exon 9 of 10	1	NM_001387468.1	ENSP00000339207.6

Frequencies

GnomAD3 genomes AF: 0.0000539 AC: 6 AN: 111242 Hom.: 0 Cov.: 23

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: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000270 AC: 48 AN: 177872 AF XY: 0.000415

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000531

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000745

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.000136 AC: 148 AN: 1086265 Hom.: 0 Cov.: 27 AF XY: 0.000229 AC XY: 81 AN XY: 354083

African (AFR) AF: 0.00 AC: 0 AN: 26233

American (AMR) AF: 0.000518 AC: 18 AN: 34765

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19110

East Asian (EAS) AF: 0.00 AC: 0 AN: 30039

South Asian (SAS) AF: 0.00213 AC: 111 AN: 52173

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.0000168 AC: 14 AN: 834728

Other (OTH) AF: 0.000110 AC: 5 AN: 45587

GnomAD4 genome AF: 0.0000449 AC: 5 AN: 111293 Hom.: 0 Cov.: 23 AF XY: 0.000149 AC XY: 5 AN XY: 33503

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 10386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00190 AC: 5 AN: 2629

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5887

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53051

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.0000368 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.631G>A (p.A211T) alteration is located in exon 9 (coding exon 9) of the FAM122B gene. This alteration results from a G to A substitution at nucleotide position 631, causing the alanine (A) at amino acid position 211 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	Benign	0.063
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.011
DANN	Benign	0.59
DEOGEN2	Benign	0.070	T;T;.;.;.;T
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.82	T;T;T;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0044	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
PhyloP100		-0.095
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.13	N;.;N;N;.;.
REVEL	Benign	0.047
Sift	Benign	0.43	T;.;T;T;.;.
Sift4G	Benign	0.66	T;T;T;T;T;T
Polyphen		0.019	B;.;.;B;B;.
Vest4		0.088
MutPred		0.065		Gain of relative solvent accessibility (P = 0.0215);.;.;.;.;.;
MVP		0.20
MPC		0.61
ClinPred		0.0060	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.036
gMVP		0.19
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757171918; hg19: chrX-133915876;